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1
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Ye RQ, Chen YF, Ma C, Cheng X, Guo W, Li S. Advances in identifying risk factors of metabolic dysfunction-associated alcohol-related liver disease. Biomed Pharmacother 2025; 188:118191. [PMID: 40408808 DOI: 10.1016/j.biopha.2025.118191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 05/13/2025] [Accepted: 05/21/2025] [Indexed: 05/25/2025] Open
Abstract
Metabolic dysfunction-associated alcohol-related liver disease (MetALD) is an emerging clinical entity that reflects the coexistence of metabolic dysfunction and alcohol-related liver injury. Unlike classical alcoholic liver disease (ALD), MetALD patients often present with lower to moderate alcohol consumption alongside metabolic risk factors such as obesity, insulin resistance, and dyslipidemia. These factors can synergistically worsen liver injury even at lower alcohol intake levels. Alcohol abuse remains a major global health concern, with the liver being the primary target of alcohol's toxic effects. Long-term alcohol exposure, especially when compounded by metabolic dysfunction, can accelerate the progression from steatosis to inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Besides alcohol itself, various factors, including genetic predispositions, gender, type of alcoholic beverage, drinking patterns, and co-morbidities such as viral infections (HBV, HCV) modulate disease susceptibility and severity. This review summarizes current knowledge of risk factors contributing to MetALD, highlights the synergistic interactions between metabolic dysfunction and alcohol consumption, and discusses potential strategies for disease prevention and management.
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Affiliation(s)
- Rui-Qi Ye
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China; Xinhua Clinical Medical College, Shanghai Jiao Tong University, Shanghai 200135, China
| | - Yi-Fan Chen
- College of Basic Medical Sciences, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Chang Ma
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xi Cheng
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wei Guo
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
| | - Sha Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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Seitz HK. A narrative review on alcohol and alimentary tract cancer with special emphasis on acetaldehyde and oxidative stress. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025. [PMID: 40378880 DOI: 10.1055/a-2588-6849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/19/2025]
Abstract
Approximately 4% of all cancer cases worldwide are caused by alcohol consumption (oropharynx, larynx, esophagus, stomach, colorectum, liver and the female breast). Various mechanisms contribute to ethanol-mediated carcinogenesis, including the action of acetaldehyde, the first metabolite of ethanol oxidation and oxidative stress primarily promoted through the induction of cytochrome P4502E1. Acetaldehyde is toxic and carcinogenic, binds to DNA and proteins, inhibits the oxidative defense- and the nuclear repair system, and prevents DNA methylation. High levels of acetaldehyde occur through increased production in the presence of a hyperactive alcohol dehydrogenase (ADH1C*1,1) or decreased degradation in the presence of low active aldehyde dehydrogenase (ALDH2*1,2). In addition, microbes of the upper alimentary tract and the colorectum effectively produce acetaldehyde from ethanol. In addition, ethanol induces cytochrome P4502E1 resulting in an enhanced ethanol metabolism and the generation of reactive oxygen species (ROS). ROS may cause lipid peroxidation (LPO) with the LPO-products 4-hydroxynonenal or malondialdehyde, which may form highly carcinogenic etheno DNA-adducts CYP2E1 is also involved in the activation of a variety of dietary and tobacco procarcinogens and in the degradation of retinoic acid. Alcohol also influences tumor promotion, such as epigenetics with a change in DNA methylation and histone modification, and affects a variety of cancer genes and signaling pathways. Preventive measures include reducing alcohol consumption, quitting smoking and keeping good oral hygiene. Alcohol consumers - especially when they smoke or belong to genetic risk groups - should be regularly checked for cancer of the upper alimentary tract, for alcohol- associated liver disease, and for breast cancer. Cessation or reduction of alcohol consumption definitively reduces cancer risk.
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Affiliation(s)
- Helmut Karl Seitz
- Centre of Liver- and Alcohol Diseases, ETHIANUM Klinik, Heidelberg, Germany
- Internal Medicine, Gastroenetrology, Alcohol Research, Faculty of Medicine, University of Heidelberg, Heidelberg, Germany
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3
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Yang K, Beaudoin JJ, Howell BA, Mullin J, Amini E, Lai JCK, Gelotte CK, Sista S, Atillasoy E. Quantitative Systems Toxicology Modeling of Acetaminophen Pharmacokinetics and Hepatic Biomarkers After Overdoses of Extended-Release and Immediate-Release Formulations in Adults With Chronic Alcohol Use or Low Glutathione. CPT Pharmacometrics Syst Pharmacol 2025. [PMID: 40365931 DOI: 10.1002/psp4.70045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/02/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
Acetaminophen (APAP), an over-the-counter analgesic and antipyretic, can cause hepatotoxicity when ingested in large overdoses. APAP has multiple formulations including immediate-release (IR) and extended-release (ER) preparations. A recently published consensus statement on the management of APAP poisoning indicated that management of APAP-ER overdose is the same as that for APAP-IR overdose. Consistent with this consensus, it was previously reported that quantitative systems toxicology (QST) modeling using DILIsym predicted similar pharmacokinetic (PK) and hepatic biomarker profiles for the APAP-ER and APAP-IR formulations after overdose in healthy adults. Hepatic injury from APAP is caused by the reactive metabolite, N-acetyl-ρ-benzoquinone imine (NAPQI), which is formed predominantly by CYP2E1-mediated metabolism and eliminated by hepatic glutathione. As such, conditions that can increase NAPQI production (e.g., CYP2E1 induction by alcohol) or decrease hepatic glutathione stores (e.g., underling liver disease) may impact PK and susceptibility to hepatotoxicity after overdose of APAP-IR and APAP-ER. In the current study, APAP-IR and APAP-ER models in chronic alcohol users and individuals with low hepatic glutathione were developed and verified within DILIsym. Simulations using verified models predicted similar PK and hepatic biomarker profiles for the APAP-ER and APAP-IR formulations in moderate and excessive chronic alcohol users and adults with low hepatic glutathione levels after single acute overdoses up to ~100 g and repeat supratherapeutic ingestions (up to 7.8 g/day for 10 days). These results further support that approaches to manage APAP-IR overdoses can be applied to manage APAP-ER overdoses in adults with chronic alcohol consumption or lower hepatic glutathione levels.
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Affiliation(s)
- Kyunghee Yang
- Quantitative Systems Pharmacology Solutions, Simulations Plus Inc., Research Triangle Park, North Carolina, USA
| | - James J Beaudoin
- Quantitative Systems Pharmacology Solutions, Simulations Plus Inc., Research Triangle Park, North Carolina, USA
| | - Brett A Howell
- Quantitative Systems Pharmacology Solutions, Simulations Plus Inc., Research Triangle Park, North Carolina, USA
| | - James Mullin
- Physiologically-Based Pharmacokinetics Solutions, Simulations Plus Inc., Research Triangle Park, North Carolina, USA
| | - Elham Amini
- Physiologically-Based Pharmacokinetics Solutions, Simulations Plus Inc., Research Triangle Park, North Carolina, USA
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Zakhari S, Neuman M, Seitz HK. The role of cytochrome P4502E1 in ethanol mediated diseases: a narrative update. Alcohol Alcohol 2025; 60:agaf014. [PMID: 40192654 DOI: 10.1093/alcalc/agaf014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/21/2025] [Accepted: 03/08/2025] [Indexed: 05/17/2025] Open
Abstract
Cytochrome P450 (CYPs) superfamily of enzymes metabolize thousands of endogenous and exogenous substrates including ethanol. Results: Cytochrome P4502E1 (CYP2E1) is involved in ethanol metabolism as part of the so-called microsomal ethanol metabolizing system, in the metabolism of fatty acids and some drugs such as acetaminophen and isoniazid, and in the activation of a variety of procarcinogens (PCs). Chronic ethanol consumption induces CYP2E1 which may result in an enhanced metabolism of these drugs to their toxic intermediates, and in the generation of carcinogens. In addition, ethanol oxidation increases and is associated with the generation of reactive oxygen species (ROS). This oxidative stress is an important driver for the development of alcohol-associated liver disease (AALD) and alcohol-mediated cancer (AMC). ROS may bind directly to proteins and to DNA. ROS may also lead to lipid peroxidation (LPO) with the generation of LPO products. These LPO products may bind to DNA forming etheno-DNA adducts. Cell culture studies as well as animal experiments have shown that CYP2E1 knock-out animals or the inhibition of CYP2E1 by chemicals results in a significant improvement of liver histology. CYP2E1 is also involved in pathogenesis of hepatic steatosis and fibrosis. More recent studies in patients with AALD have demonstrated an improvement of serum transaminase activities when CYP2E1 was inhibited by clomethiazole. In addition to its role in the generation of ROS, CYP2E1 also enhances the activation of PCs and decreases the level of retinol and retinoic acid in the liver. Conclusion: Inhibition of CYP2E1 may improve AALD and may inhibit AMC.
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Affiliation(s)
- Samir Zakhari
- Independent Researcher, Washington, DC, University Park, 20782, USA
| | - Manuela Neuman
- In Vitro Drug Safety and Biotechnology, Toronto, ON, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
| | - Helmut K Seitz
- Centre of Liver and Alcohol Diseases, Ethianum Clinic, Heidelberg, Germany
- Faculty of Medicine, University of Heidelberg, Heidelberg, Germany
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Zhou X, Wang J, Zhou S. Poria cocos polysaccharides improve alcoholic liver disease by interfering with ferroptosis through NRF2 regulation. Aging (Albany NY) 2024; 16:6147-6162. [PMID: 38507458 PMCID: PMC11042950 DOI: 10.18632/aging.205693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 03/01/2024] [Indexed: 03/22/2024]
Abstract
The active ingredient in Poria cocos, a parasitic plant belonging to the family Polyporaceae, is Poria cocos polysaccharide (PCP). PCP exhibits liver protection and anti-inflammatory effects, although its effect on alcoholic liver disease (ALD) remains unstudied. This study investigated the mechanism of PCP in improving ALD by regulating the Nrf2 signaling pathway. After daily intragastric administration of high-grade liquor for 4 hours, each drug group received PCPs or the ferroptosis inhibitor ferrostatin-1. The Nrf2 inhibitor ML385 (100 mg/kg/day) group was intraperitoneally injected, after which PCP (100 mg/kg/day) was administered by gavage. Samples were collected after 6 weeks for liver function and blood lipid analysis using an automatic biochemical analyzer. In the alcoholic liver injury cell model established with 150 mM alcohol, the drug group was pretreated with PCP, Fer-1, and ML385, and subsequent results were analyzed. The results revealed that PCP intervention significantly reduced liver function and blood lipid levels in alcohol-fed rats, along with decreased lipid deposition. PCP notably enhanced Nrf2 signaling expression, regulated oxidative stress levels, inhibited NF-κβ, and its downstream inflammatory signaling pathways. Furthermore, PCP upregulated FTH1 protein expression and reduced intracellular Fe2+, suggesting an improvement in ferroptosis. In vitro studies yielded similar results, indicating that PCP can reduce intracellular ferroptosis by regulating oxidative stress and improve alcoholic liver injury by inhibiting the production of inflammatory factors.
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Affiliation(s)
- Xiangyu Zhou
- Guizhou University of Traditional Chinese Medicine, Guiyang 550002, China
- The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, China
| | - Jincheng Wang
- Guizhou University of Traditional Chinese Medicine, Guiyang 550002, China
- The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, China
| | - Sufang Zhou
- The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, China
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Nguyen LTD, Gunathilake M, Lee J, Oh JH, Chang HJ, Sohn DK, Shin A, Kim J. Zinc intake, SLC30A8 rs3802177 polymorphism, and colorectal cancer risk in a Korean population: a case-control study. J Cancer Res Clin Oncol 2023; 149:16429-16440. [PMID: 37707576 DOI: 10.1007/s00432-023-05381-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 08/30/2023] [Indexed: 09/15/2023]
Abstract
PURPOSE Zinc is an essential micronutrient involving in multiple enzymatic reactions of human metabolism and biological functions affecting the cancer development. However, the relationship between dietary zinc intake and colorectal cancer (CRC) risk has been unclear. Herein, our study investigated the relationship between dietary zinc intake and CRC risk, and examined how the SLC30A8 rs3802177 genetic variant affects this association. METHODS A total of 1431 CRC cases and 2704 controls were selected to investigate the relationship between dietary zinc intake and CRC risk. After excluding individuals without genotype data, 1097 CRC cases and 1559 controls were used to evaluate the interaction between dietary zinc intake and the rs3802177 polymorphism in CRC risk. The odds ratios (ORs) and 95% confidence intervals (CIs) were measured using unconditional logistic regression models. RESULTS Higher dietary zinc intake was inversely associated with the risk of CRC in the total population [adjusted OR (aOR) = 0.80, 95% CI 0.66-0.96, p for trend = 0.018]. In the codominant model, G+ carriers of the SLC30A8 rs3802177 with higher consumption of zinc were observed to have a significantly lower risk of CRC in all participants (p for interaction = 0.020). In females, GG carriers with higher zinc intake showed a stronger protective effect against the development of CRC (p for interaction = 0.008). CONCLUSIONS In summary, our findings suggest an inverse association between dietary zinc intake and CRC risk, and this relationship may be modified by SLC30A8 rs3802177 polymorphism.
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Affiliation(s)
- Linh Thi Dieu Nguyen
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu, Goyang-Si, Gyeonggi-Do, 10408, Republic of Korea
| | - Madhawa Gunathilake
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu, Goyang-Si, Gyeonggi-Do, 10408, Republic of Korea
| | - Jeonghee Lee
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu, Goyang-Si, Gyeonggi-Do, 10408, Republic of Korea
| | - Jae Hwan Oh
- Center for Colorectal Cancer, National Cancer Center Hospital, National Cancer Center, Goyang-Si, Gyeonggi-Do, South Korea
| | - Hee Jin Chang
- Center for Colorectal Cancer, National Cancer Center Hospital, National Cancer Center, Goyang-Si, Gyeonggi-Do, South Korea
| | - Dae Kyung Sohn
- Center for Colorectal Cancer, National Cancer Center Hospital, National Cancer Center, Goyang-Si, Gyeonggi-Do, South Korea
| | - Aesun Shin
- Department of Preventive Medicine, Seoul National University College of Medicine, Jongno-Gu, Seoul, South Korea
| | - Jeongseon Kim
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu, Goyang-Si, Gyeonggi-Do, 10408, Republic of Korea.
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7
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Park Y, Kang D, Sinn DH, Kim H, Hong YS, Cho J, Gwak GY. Effect of lifestyle modification on hepatocellular carcinoma incidence and mortality among patients with chronic hepatitis B. World J Gastroenterol 2023; 29:3843-3854. [PMID: 37426323 PMCID: PMC10324530 DOI: 10.3748/wjg.v29.i24.3843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/13/2023] [Accepted: 05/25/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Research exploring the influence of healthier lifestyle modification (LSM) on the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) is limited.
AIM To emulate a target trial to determine the effect of LSM on HCC incidence and mortality among patients with CHB by large-scale population-based observational data.
METHODS Among the patients with CHB enrolled in the Korean National Health Insurance Service between January 1, 2009, and December 31, 2017, those aged ≥ 20 years who drank alcohol, smoked cigarettes, and were sedentary were analyzed. Exposure included at least one LSM, including alcohol abstinence, smoking cessation, and regular exercise. The primary outcome was HCC development, and the secondary outcome was liver-related mortality. We used 2:1 propensity score matching to account for covariates.
RESULTS With 48766 patients in the LSM group and 103560 in the control group, the adjusted hazard ratio (HR) for incident HCC and liver-related mortality was 0.92 [95% confidence interval (CI): 0.87-0.96] and 0.92 (95%CI: 0.86-0.99) in the LSM group, respectively, compared with the control group. Among the LSM group, the adjusted HR (95%CI) for incident HCC was 0.84 (0.76-0.94), 0.87 (0.81-0.94), and 1.08 (1.00-1.16) for alcohol abstinence, smoking cessation, and regular exercise, respectively. The adjusted HR (95%CI) for liver-related mortality was 0.92 (0.80-1.06), 0.81 (0.72-0.91), and 1.15 (1.04-1.27) for alcohol abstinence, smoking cessation, and regular exercise, respectively.
CONCLUSION LSM lowered the risk of HCC and mortality in patients with CHB. Thus, active LSM, particularly alcohol abstinence and smoking cessation, should be encouraged in patients with CHB.
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Affiliation(s)
- Yewan Park
- Department of Internal Medicine, Kyung Hee University Hospital, Seoul 02447, South Korea
- Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul 06355, South Korea
| | - Danbee Kang
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul 06355, South Korea
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, South Korea
| | - Dong Hyun Sinn
- Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul 06355, South Korea
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
| | - Hyunsoo Kim
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, South Korea
| | - Yun Soo Hong
- Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD 21287, United States
| | - Juhee Cho
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul 06355, South Korea
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, South Korea
- Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD 21287, United States
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
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Odriozola A, Santos-Laso A, Del Barrio M, Cabezas J, Iruzubieta P, Arias-Loste MT, Rivas C, Duque JCR, Antón Á, Fábrega E, Crespo J. Fatty Liver Disease, Metabolism and Alcohol Interplay: A Comprehensive Review. Int J Mol Sci 2023; 24:ijms24097791. [PMID: 37175497 PMCID: PMC10178387 DOI: 10.3390/ijms24097791] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 05/15/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, and its incidence has been increasing in recent years because of the high prevalence of obesity and metabolic syndrome in the Western population. Alcohol-related liver disease (ArLD) is the most common cause of cirrhosis and constitutes the leading cause of cirrhosis-related deaths worldwide. Both NAFLD and ArLD constitute well-known causes of liver damage, with some similarities in their pathophysiology. For this reason, they can lead to the progression of liver disease, being responsible for a high proportion of liver-related events and liver-related deaths. Whether ArLD impacts the prognosis and progression of liver damage in patients with NAFLD is still a matter of debate. Nowadays, the synergistic deleterious effect of obesity and diabetes is clearly established in patients with ArLD and heavy alcohol consumption. However, it is still unknown whether low to moderate amounts of alcohol are good or bad for liver health. The measurement and identification of the possible synergistic deleterious effect of alcohol consumption in the assessment of patients with NAFLD is crucial for clinicians, since early intervention, advising abstinence and controlling cardiovascular risk factors would improve the prognosis of patients with both comorbidities. This article seeks to perform a comprehensive review of the pathophysiology of both disorders and measure the impact of alcohol consumption in patients with NAFLD.
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Affiliation(s)
- Aitor Odriozola
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Alvaro Santos-Laso
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - María Del Barrio
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Joaquín Cabezas
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Paula Iruzubieta
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - María Teresa Arias-Loste
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Coral Rivas
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Juan Carlos Rodríguez Duque
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Ángela Antón
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Emilio Fábrega
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Javier Crespo
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
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Hohmann N, Schröder F, Moreira B, Teng H, Burhenne J, Bruckner T, Mueller S, Haefeli WE, Seitz HK. Effect of Clomethiazole Vs. Clorazepate on Hepatic Fat and Serum Transaminase Activities in Alcohol-Associated Liver Disease: Results from a Randomized, Controlled Phase II Clinical Trial. Alcohol Alcohol 2023; 58:134-141. [PMID: 36562601 DOI: 10.1093/alcalc/agac068] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 10/27/2022] [Accepted: 11/21/2022] [Indexed: 12/24/2022] Open
Abstract
AIMS Alcohol-associated liver disease (ALD) is a global health problem caused, among other factors, by oxidative stress from the formation of reactive oxygen species (ROS). One important source of ROS is microsomal ethanol metabolism catalyzed by cytochrome P450 2E1 (CYP2E1), which is induced by chronic ethanol consumption. Inhibition of CYP2E1 by clomethiazole (CMZ) decreases oxidative stress in cell cultures and improves ALD in animal studies. Our study aimed to assess the benefits of a CYP2E1 inhibitor (clomethiazole) in detoxification of patients with ALD. METHODS Open label, randomized controlled clinical trial to study whether CYP2E1 inhibition improves ALD in the patients with alcohol use disorders admitted for alcohol detoxification therapy (ADT). Patients had to have a serum aspartate aminotransferase (AST) activity exceeding twice the upper normal limit at time of admission and be non-cirrhotic defined by fibroscan value <12 kPa. Sixty patients were randomly assigned to ADT with either CMZ or clorazepate (CZP) for 7-10 days in a 1:1 ratio. The chlorzoxazone test of CYP2E1 activity was performed at enrolment and at 2 points during the study. RESULTS ADT improved hepatic steatosis (controlled attenuation parameter) in both groups significantly. A trend towards a greater improvement in hepatic fat content during ADT (-21.5%) was observed in the CMZ group (252 ± 48 dB/m vs. 321 ± 38 dB/m; P < 0.0001) compared with the CZP group (-13.9%; 273 ± 38 dB/m vs. 317 ± 39 dB/m; P < 0.0001). As already reported, serum AST (P < 0.004) and alanine aminotransferase (ALT) activities (P < 0.0006) significantly decreased in CMZ patients as compared with patients on CZP by the end of hospitalization. A significant correlation was found between AST (P = 0.023), ALT (P = 0.009), GGT (P = 0.039) and CAP. CONCLUSION This study demonstrates that CMZ improves clinical biomarkers for ALD in humans most likely due to its inhibitory effect on CYP2E1. Because of its addictive potential, CMZ can only be given for a short period of time and therefore other CYP2E1 inhibitors to treat ALD are needed.
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Affiliation(s)
- Nicolas Hohmann
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg 69120, Germany
| | - Fabian Schröder
- Centre of Alcohol Research (CAR) University of Heidelberg, Germany, and Department of Medicine, Salem Medical Centre, Heidelberg 69121, Germany
| | - Bernardo Moreira
- Centre of Alcohol Research (CAR) University of Heidelberg, Germany, and Department of Medicine, Salem Medical Centre, Heidelberg 69121, Germany
| | - Haidong Teng
- Centre of Alcohol Research (CAR) University of Heidelberg, Germany, and Department of Medicine, Salem Medical Centre, Heidelberg 69121, Germany
| | - Jürgen Burhenne
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg 69120, Germany
| | - Thomas Bruckner
- Institute for Medical Biometry and Informatics, Heidelberg University, Heidelberg 69120, Germany
| | - Sebastian Mueller
- Centre of Alcohol Research (CAR) University of Heidelberg, Germany, and Department of Medicine, Salem Medical Centre, Heidelberg 69121, Germany
| | - Walter E Haefeli
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg 69120, Germany
| | - Helmut K Seitz
- Centre of Alcohol Research (CAR) University of Heidelberg, Germany, and Department of Medicine, Salem Medical Centre, Heidelberg 69121, Germany
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10
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Cao L, Wu D, Qin L, Tan D, Fan Q, Jia X, Yang M, Zhou T, Feng C, Lu Y, He Y. Single-Cell RNA Transcriptome Profiling of Liver Cells of Short-Term Alcoholic Liver Injury in Mice. Int J Mol Sci 2023; 24:ijms24054344. [PMID: 36901774 PMCID: PMC10002329 DOI: 10.3390/ijms24054344] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/23/2023] [Accepted: 02/20/2023] [Indexed: 02/24/2023] Open
Abstract
Alcoholic liver disease (ALD) is currently considered a global healthcare problem with limited pharmacological treatment options. There are abundant cell types in the liver, such as hepatocytes, endothelial cells, Kupffer cells and so on, but little is known about which kind of liver cells play the most important role in the process of ALD. To obtain a cellular resolution of alcoholic liver injury pathogenesis, 51,619 liver single-cell transcriptomes (scRNA-seq) with different alcohol consumption durations were investigated, 12 liver cell types were identified, and the cellular and molecular mechanisms of the alcoholic liver injury were revealed. We found that more aberrantly differential expressed genes (DEGs) were present in hepatocytes, endothelial cells, and Kupffer cells than in other cell types in alcoholic treatment mice. Alcohol promoted the pathological processes of liver injury; the specific mechanisms involved: lipid metabolism, oxidative stress, hypoxia, complementation and anticoagulation, and hepatocyte energy metabolism on hepatocytes; NO production, immune regulation, epithelial and cell migration on endothelial cells; antigen presentation and energy metabolism on Kupffer cells, based on the GO analysis. In addition, our results showed that some transcription factors (TFs) are activated in alcohol-treated mice. In conclusion, our study improves the understanding of liver cell heterogeneity in alcohol-fed mice at the single-cell level. It has potential value for understanding key molecular mechanisms and improving current prevention and treatment strategies for short-term alcoholic liver injury.
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Affiliation(s)
- Ligang Cao
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Di Wu
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Lin Qin
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Daopeng Tan
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Qingjie Fan
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Xiaohuan Jia
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Mengting Yang
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Tingting Zhou
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Chengcheng Feng
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Yanliu Lu
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Yuqi He
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
- Correspondence:
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11
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Kuendee N, Naladta A, Kulsirirat T, Yimsoo T, Yingmema W, Pansuksan K, Sathirakul K, Sukprasert S. Lysiphyllum strychnifolium (Craib) A. Schmitz Extracts Moderate the Expression of Drug-Metabolizing Enzymes: In Vivo Study to Clinical Propose. Pharmaceuticals (Basel) 2023; 16:237. [PMID: 37259384 PMCID: PMC9961159 DOI: 10.3390/ph16020237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 01/27/2023] [Accepted: 02/01/2023] [Indexed: 09/14/2024] Open
Abstract
Lysiphyllum strychnifolium (Craib) A. Schmitz (LS) has been traditionally used as a medicinal herb by folk healers in Thailand with rare evidence-based support. Hepatic cytochrome P450s (CYPs450) are well known as the drug-metabolizing enzymes that catalyze all drugs and toxicants. In this study, we investigated the mRNA levels of six clinically important CYPs450, i.e., CYP1A2, 3A2, 2C11, 2D1, 2D2, and 2E1, in rats given LS extracts. Seventy Wistar rats were randomized into seven groups (n = 10). Each group was given LS stem ethanol (SE) and leaf water (LW) extracts orally at doses of 300, 2000, and 5000 mg/kg body weight (mg/kg.bw) for twenty-eight consecutive days. After treatment, the expression of CYPs450 genes was measured using quantitative real-time PCR. The results revealed that SE and LW, which contained quercetin and gallic acid, promoted the upregulation of all CYPs450. Almost all CYPs450 genes were downregulated in all male LW-treated rats but upregulated in female-treated groups, suggesting that CYP gene expressions in LS-treated rats were influenced by gender. Moderate and high doses of the LS extracts had a tendency to induce six CYP450s' transcription levels in both rat genders. CYP2E1 gene showed a unique expression level in male rats receiving SE at a dose of 2000 mg/kg.bw, whereas a low dose of 300 mg/kg.bw was found in the LW-treated female group. As a result, our findings suggest that different doses of LS extracts can moderate the varying mRNA expression of clinically relevant CYP genes. In this study, we provide information about CYP induction and inhibition in vivo, which could be a desirable condition for furthering the practical use of LS extracts in humans.
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Affiliation(s)
- Natthaporn Kuendee
- Faculty of Veterinary Medicine, Rajamangala University of Technology Tawan-ok, Chonburi 20110, Thailand
| | - Alisa Naladta
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Thitianan Kulsirirat
- Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
| | - Thunyatorn Yimsoo
- Animal Center, Thammasat University (Rangsit Campus), Pathum Thani 12120, Thailand
| | - Werayut Yingmema
- Animal Center, Thammasat University (Rangsit Campus), Pathum Thani 12120, Thailand
| | - Kanoktip Pansuksan
- Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathum Thani 12120, Thailand
| | - Korbtham Sathirakul
- Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
| | - Sophida Sukprasert
- Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathum Thani 12120, Thailand
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12
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Galacto-Oligosaccharide Alleviates Alcohol-Induced Liver Injury by Inhibiting Oxidative Stress and Inflammation. Metabolites 2022; 12:metabo12090867. [PMID: 36144271 PMCID: PMC9506531 DOI: 10.3390/metabo12090867] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/09/2022] [Accepted: 09/10/2022] [Indexed: 11/16/2022] Open
Abstract
Alcoholic liver disease (ALD) is a primary cause of mortality and morbidity worldwide. Oxidative stress and inflammation are important pathogenic factors contributing to ALD. We investigated the protective mechanism of galacto-oligosaccharide (GOS) against ALD through their antioxidant and anti-inflammatory activities by performing in vivo and in vitro experiments. Western blot and RT‒PCR results indicated that the expression of cytochrome P450 protein 2E1 (CYP2E1) in liver tissues and L02 cells was reduced in the GOS-treated mice compared with the model group. In addition, GOS prominently reduced the expression of Kelch-like ECH-associated protein 1 (Keap1), increased the expression of the nuclear factor erythroid-2-related factor 2 (Nrf2) and haem oxygenase-1 (HO-1) proteins, and enhanced the antioxidant capacity. In addition, GOS decreased inflammation by reducing inflammatory factor levels and inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) pathway. Based on these results, GOS may be a prospective functional food for the prevention and treatment of ALD.
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13
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Hepatic, Extrahepatic and Extracellular Vesicle Cytochrome P450 2E1 in Alcohol and Acetaminophen-Mediated Adverse Interactions and Potential Treatment Options. Cells 2022; 11:cells11172620. [PMID: 36078027 PMCID: PMC9454765 DOI: 10.3390/cells11172620] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/03/2022] [Accepted: 08/19/2022] [Indexed: 12/15/2022] Open
Abstract
Alcohol and several therapeutic drugs, including acetaminophen, are metabolized by cytochrome P450 2E1 (CYP2E1) into toxic compounds. At low levels, these compounds are not detrimental, but higher sustained levels of these compounds can lead to life-long problems such as cytotoxicity, organ damage, and cancer. Furthermore, CYP2E1 can facilitate or enhance the effects of alcohol-drug and drug-drug interactions. In this review, we discuss the role of CYP2E1 in the metabolism of alcohol and drugs (with emphasis on acetaminophen), mediating injury/toxicities, and drug-drug/alcohol-drug interactions. Next, we discuss various compounds and various nutraceuticals that can reduce or prevent alcohol/drug-induced toxicity. Additionally, we highlight experimental outcomes of alcohol/drug-induced toxicity and potential treatment strategies. Finally, we cover the role and implications of extracellular vesicles (EVs) containing CYP2E1 in hepatic and extrahepatic cells and provide perspectives on the clinical relevance of EVs containing CYP2E1 in intracellular and intercellular communications leading to drug-drug and alcohol-drug interactions. Furthermore, we provide our perspectives on CYP2E1 as a druggable target using nutraceuticals and the use of EVs for targeted drug delivery in extrahepatic and hepatic cells, especially to treat cellular toxicity.
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14
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Yoo JE, Han K, Shin DW, Kim D, Kim BS, Chun S, Jeon KH, Jung W, Park J, Park JH, Choi KS, Kim JS. Association Between Changes in Alcohol Consumption and Cancer Risk. JAMA Netw Open 2022; 5:e2228544. [PMID: 36001313 PMCID: PMC9403779 DOI: 10.1001/jamanetworkopen.2022.28544] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
IMPORTANCE Although numerous studies have shown an association between alcohol consumption and cancer, how changes in drinking behavior increase or decrease the incidence of cancer is not well understood. OBJECTIVE To investigate the association between the reduction, cessation, or increase of alcohol consumption and the development of alcohol-related cancers and all cancers. DESIGN, SETTING, AND PARTICIPANTS This population-based cohort study analyzed adult beneficiaries in the Korean National Health Insurance Service. Participants (aged ≥40 years) included those who underwent a national health screening in both 2009 and 2011 and had available data on their drinking status. Data were analyzed from April 16 to July 6, 2020. EXPOSURES Alcohol consumption level, which was self-reported by participants in health screening questionnaires, was categorized into none (0 g/d), mild (<15 g/d), moderate (15-29.9 g/d), and heavy (≥30 g/d) drinking. Based on changes in alcohol consumption level from 2009 to 2011, participants were categorized into the following groups: nondrinker, sustainer, increaser, quitter, and reducer. MAIN OUTCOMES AND MEASURES The primary outcome was newly diagnosed alcohol-related cancers (including cancers of the head and neck, esophagus, colorectum, liver, larynx, and female breast), and the secondary outcome was all newly diagnosed cancers (except for thyroid cancer). RESULTS Among the 4 513 746 participants (mean [SD] age, 53.6 [9.6] years; 2 324 172 [51.5%] men), the incidence rate of cancer was 7.7 per 1000 person-years during a median (IQR) follow-up of 6.4 (6.1-6.6) years. Compared with the sustainer groups at each drinking level, the increaser groups had a higher risk of alcohol-related cancers and all cancers. The increased alcohol-related cancer incidence was associated with dose; those who changed from nondrinking to mild (adjusted hazard ratio [aHR], 1.03; 95% CI, 1.00-1.06), moderate (aHR, 1.10; 95% CI, 1.02-1.18), or heavy (aHR, 1.34; 95% CI, 1.23-1.45) drinking levels had an associated higher risk than those who did not drink. Those with mild drinking levels who quit drinking had a lower risk of alcohol-related cancer (aHR, 0.96; 95% CI, 0.92-0.99) than those who sustained their drinking levels. Those with moderate (aHR, 1.07; 95% CI, 1.03-1.12) or heavy (aHR, 1.07; 95% CI, 1.02-1.12) drinking levels who quit drinking had a higher all cancer incidence than those who sustained their levels, but when quitting was sustained, this increase in risk disappeared. Compared with sustained heavy drinking, reduced heavy drinking levels to moderate levels (alcohol-related cancer: aHR, 0.91 [95% CI, 0.86-0.97]; all cancers: aHR, 0.96 [95% CI, 0.92-0.99]) or mild levels (alcohol-related cancer: aHR, 0.92 [95% CI, 0.86-0.98]; all cancers: aHR, 0.92 [95% CI, 0.89-0.96]) were associated with decreased cancer risk. CONCLUSIONS AND RELEVANCE Results of this study showed that increased alcohol consumption was associated with higher risks for alcohol-related and all cancers, whereas sustained quitting and reduced drinking were associated with lower risks of alcohol-related and all cancers. Alcohol cessation and reduction should be reinforced for the prevention of cancer.
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Affiliation(s)
- Jung Eun Yoo
- Department of Family Medicine, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Dong Wook Shin
- Department of Supportive Care Center/Department of Family Medicine, Samsung Medical Center, Seoul, Republic of Korea
- Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea
- Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
| | - Dahye Kim
- Department of Medical Statistics, The Catholic University of Korea, Seoul, Republic of Korea
| | - Bong-seong Kim
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
- Department of Medical Statistics, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sohyun Chun
- International Healthcare Center, Samsung Medical Center, Seoul, Republic of Korea
| | - Keun Hye Jeon
- Department of Family Medicine, Cha Gumi Medical Center, Cha University, Gumi-si, Gyeongsangbuk-do, Republic of Korea
| | - Wonyoung Jung
- Department of Supportive Care Center/Department of Family Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Jinsung Park
- Department of Urology, Uijeongbu Eulji Medical Center, Eulji University, Uijeongbu-si, Gyeonggi-do, Republic of Korea
| | - Jin Ho Park
- Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kui Son Choi
- Department of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
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15
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Shi Y, Liu Y, Wang S, Huang J, Luo Z, Jiang M, Lu Y, Lin Q, Liu H, Cheng N, You J. Endoplasmic reticulum-targeted inhibition of CYP2E1 with vitamin E nanoemulsions alleviates hepatocyte oxidative stress and reverses alcoholic liver disease. Biomaterials 2022; 288:121720. [DOI: 10.1016/j.biomaterials.2022.121720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/29/2022] [Accepted: 08/01/2022] [Indexed: 11/16/2022]
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16
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Lee HW, Huang D, Shin WK, de la Torre K, Song M, Shin A, Lee JK, Kang D. Frequent low dose alcohol intake increases gastric cancer risk: the Health Examinees-Gem (HEXA-G) study. Cancer Biol Med 2022; 19:j.issn.2095-3941.2021.0642. [PMID: 35484712 PMCID: PMC9425184 DOI: 10.20892/j.issn.2095-3941.2021.0642] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
OBJECTIVE Epidemiological studies indicate that alcohol increases gastric cancer (GC) risk, yet most studies have focused on heavy alcohol intake, leaving other factors understudied. A comprehensive investigation of the effects of the frequency and amount of alcohol intake may help elucidate the GC risk associated with drinking behavior. METHODS The Health Examinees-Gem (HEXA-G) study, a community-based large-scale prospective cohort study, enrolled Korean adults 40-69 years of age between the years 2004 and 2013. Incident GC cases were identified through linkage to Korea Central Cancer Registry data until December 31, 2017. Self-reported questionnaires were used to survey alcohol consumption-related factors (duration, frequency, amount, and type of alcoholic beverages). The frequency and amount of alcohol consumption were combined to explore GC risk according to 4 drinking patterns: "infrequent-light", "frequent-light", "infrequent-heavy", and "frequent-heavy". We used Cox proportional hazard models to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs), and investigate the relationship between alcohol intake and GC incidence. RESULTS A total of 128,218 participants were included in the analysis. During an average follow-up period of 8.6 years, 462 men and 385 women were diagnosed with GC. In men, current drinkers showed a 31% greater risk of GC than non-drinkers (HR 1.31, 95% CI 1.03-1.66), whereas no significant association was observed in women. In men, GC risk was associated with a higher frequency (P trend 0.02) and dose of ethanol intake in grams (P trend 0.03). In men, the "frequent-light" (≥5 times/week and <40 g ethanol/day) drinking pattern was associated with a 46% greater risk of GC (HR 1.46, 95% CI 1.02-2.07) than the "infrequent-light" pattern (<5 times/week and <40 g ethanol/day). CONCLUSIONS This study suggests that frequent intake of alcohol, even in low quantities per session, increases GC risk. Further research is warranted to evaluate the relationship between alcohol and GC in detail.
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Affiliation(s)
- Hwi-Won Lee
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea.,Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Dan Huang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea.,Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul 03080, Korea
| | - Woo-Kyoung Shin
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea.,Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul 03080, Korea
| | - Katherine de la Torre
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea.,Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Minkyo Song
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Aesun Shin
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jong-Koo Lee
- Department of Family Medicine, Seoul National University Hospital, Seoul 03080, Korea
| | - Daehee Kang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea.,Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul 03080, Korea
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17
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Hohmann N, Schröder F, Moreira B, Teng H, Burhenne J, Bruckner T, Mueller S, Haefeli WE, Seitz HK. Clomethiazole inhibits cytochrome P450 2E1 and improves alcoholic liver disease. Gut 2022; 71:842-844. [PMID: 33972357 DOI: 10.1136/gutjnl-2021-324727] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/30/2021] [Accepted: 05/01/2021] [Indexed: 12/20/2022]
Affiliation(s)
- Nicolas Hohmann
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University, Heidelberg, Germany
| | - Fabian Schröder
- Department of Medicine, Krankenhaus Salem, Heidelberg, Baden-Württemberg, Germany
| | - Bernardo Moreira
- Department of Medicine, Krankenhaus Salem, Heidelberg, Baden-Württemberg, Germany
| | - Haidong Teng
- Department of Medicine, Krankenhaus Salem, Heidelberg, Baden-Württemberg, Germany
| | - Jürgen Burhenne
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University, Heidelberg, Germany
| | - Thomas Bruckner
- Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Baden-Württemberg, Germany
| | - Sebastian Mueller
- Department of Medicine, Krankenhaus Salem, Heidelberg, Baden-Württemberg, Germany
| | - Walter E Haefeli
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University, Heidelberg, Germany
| | - Helmut K Seitz
- Krankenhaus Salem, Heidelberg, Baden-Württemberg, Germany
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18
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Ferdouse A, Agrawal RR, Gao MA, Jiang H, Blaner WS, Clugston RD. Alcohol induced hepatic retinoid depletion is associated with the induction of multiple retinoid catabolizing cytochrome P450 enzymes. PLoS One 2022; 17:e0261675. [PMID: 35030193 PMCID: PMC8759667 DOI: 10.1371/journal.pone.0261675] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 12/08/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic alcohol consumption leads to a spectrum of liver disease that is associated with significant global mortality and morbidity. Alcohol is known to deplete hepatic vitamin A content, which has been linked to the pathogenesis of alcoholic liver disease. It has been suggested that induction of Cytochrome P450 2E1 (CYP2E1) contributes to alcohol-induced hepatic vitamin A depletion, but the possible contributions of other retinoid-catabolizing CYPs have not been well studied. The main objective of this study was to better understand alcohol-induced hepatic vitamin A depletion and test the hypothesis that alcohol-induced depletion of hepatic vitamin A is due to CYP-mediated oxidative catabolism. This hypothesis was tested in a mouse model of chronic alcohol consumption, including wild type and Cyp2e1 -/- mice. Our results show that chronic alcohol consumption is associated with decreased levels of hepatic retinol, retinyl esters, and retinoic acid. Moreover, the depletion of hepatic retinoid is associated with the induction of multiple retinoid catabolizing CYPs, including CYP26A1, and CYP26B1 in alcohol fed wild type mice. In Cyp2e1 -/- mice, alcohol-induced retinol decline is blunted but retinyl esters undergo a change in their acyl composition and decline upon alcohol exposure like WT mice. In conclusion, the alcohol induced decline in hepatic vitamin A content is associated with increased expression of multiple retinoid-catabolizing CYPs, including the retinoic acid specific hydroxylases CYP26A1 and CYP26B1.
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Affiliation(s)
- Afroza Ferdouse
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
| | - Rishi R. Agrawal
- Institute of Human Nutrition, Columbia University, New York, New York, United States of America
| | - Madeleine A. Gao
- Institute of Human Nutrition, Columbia University, New York, New York, United States of America
- Department of Medicine, Columbia University, New York, New York, United States of America
| | - Hongfeng Jiang
- Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - William S. Blaner
- Institute of Human Nutrition, Columbia University, New York, New York, United States of America
- Department of Medicine, Columbia University, New York, New York, United States of America
| | - Robin D. Clugston
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
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19
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Finelli R, Mottola F, Agarwal A. Impact of Alcohol Consumption on Male Fertility Potential: A Narrative Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 19:ijerph19010328. [PMID: 35010587 PMCID: PMC8751073 DOI: 10.3390/ijerph19010328] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/11/2021] [Accepted: 12/23/2021] [Indexed: 12/13/2022]
Abstract
Alcohol abuse disorder is a serious condition, implicating more than 15 million people aged 12 years and older in 2019 in the United States. Ethanol (or ethyl alcohol) is mainly oxidized in the liver, resulting in the synthesis of acetaldehyde and acetate, which are toxic and carcinogenic metabolites, as well as in the generation of a reductive cellular environment. Moreover, ethanol can interact with lipids, generating fatty acid ethyl esters and phosphatidylethanol, which interfere with physiological cellular pathways. This narrative review summarizes the impact of excessive alcohol consumption on male fertility by describing its metabolism and how ethanol consumption may induce cellular damage. Furthermore, the impact of alcohol consumption on hormonal regulation, semen quality, and genetic and epigenetic regulations is discussed based on evidence from animal and human studies, focusing on the consequences on the offspring. Finally, the limitations of the current evidence are discussed. Our review highlights the association between chronic alcohol consumption and poor semen quality, mainly due to the development of oxidative stress, as well as its genotoxic impact on hormonal regulation and DNA integrity, affecting the offspring’s health. New landscapes of investigation are proposed for the identification of molecular markers for alcohol-associated infertility, with a focus on advanced OMICS-based approaches applied to the analysis of semen samples.
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Affiliation(s)
- Renata Finelli
- American Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH 44106, USA;
| | - Filomena Mottola
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, 81100 Caserta, Italy;
| | - Ashok Agarwal
- American Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH 44106, USA;
- Correspondence: ; Tel.: +1-(214)-444-9485
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20
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Hoes L, Dok R, Verstrepen KJ, Nuyts S. Ethanol-Induced Cell Damage Can Result in the Development of Oral Tumors. Cancers (Basel) 2021; 13:cancers13153846. [PMID: 34359747 PMCID: PMC8345464 DOI: 10.3390/cancers13153846] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Alcohol consumption is linked to 26.4% of all lip and oral cavity cancer cases worldwide. Despite this clear causal relationship, the exact molecular mechanisms by which ethanol damages cells are still under investigation. It is well-established that the metabolism of ethanol plays an important role. Ethanol metabolism yields reactive metabolites that can directly damage the DNA. If the damage is repaired incorrectly, mutations can be fixed in the DNA sequence. Whenever mutations affect key regulatory genes, for instance cell cycle regulating genes, uncontrolled cell growth can be the consequence. Recently, global patterns of mutations have been identified. These so-called mutational signatures represent a fingerprint of the different mutational processes over time. Interestingly, there were ethanol-related signatures discovered that did not associate with ethanol metabolism. This finding highlights there might be other molecular effects of ethanol that are yet to be discovered. Abstract Alcohol consumption is an underestimated risk factor for the development of precancerous lesions in the oral cavity. Although alcohol is a well-accepted recreational drug, 26.4% of all lip and oral cavity cancers worldwide are related to heavy drinking. Molecular mechanisms underlying this carcinogenic effect of ethanol are still under investigation. An important damaging effect comes from the first metabolite of ethanol, being acetaldehyde. Concentrations of acetaldehyde detected in the oral cavity are relatively high due to the metabolization of ethanol by oral microbes. Acetaldehyde can directly damage the DNA by the formation of mutagenic DNA adducts and interstrand crosslinks. Additionally, ethanol is known to affect epigenetic methylation and acetylation patterns, which are important regulators of gene expression. Ethanol-induced hypomethylation can activate the expression of oncogenes which subsequently can result in malignant transformation. The recent identification of ethanol-related mutational signatures emphasizes the role of acetaldehyde in alcohol-associated carcinogenesis. However, not all signatures associated with alcohol intake also relate to acetaldehyde. This finding highlights that there might be other effects of ethanol yet to be discovered.
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Affiliation(s)
- Lore Hoes
- Laboratory for Systems Biology, VIB-KU Leuven Center for Microbiology, 3000 Leuven, Belgium; (L.H.); (K.J.V.)
- Laboratory of Genetics and Genomics, Centre for Microbial and Plant Genetics, KU Leuven, 3000 Leuven, Belgium
- Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, 3000 Leuven, Belgium;
| | - Rüveyda Dok
- Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, 3000 Leuven, Belgium;
| | - Kevin J. Verstrepen
- Laboratory for Systems Biology, VIB-KU Leuven Center for Microbiology, 3000 Leuven, Belgium; (L.H.); (K.J.V.)
- Laboratory of Genetics and Genomics, Centre for Microbial and Plant Genetics, KU Leuven, 3000 Leuven, Belgium
| | - Sandra Nuyts
- Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, 3000 Leuven, Belgium;
- Department of Radiation Oncology, Leuven Cancer Institute, University Hospital Leuven, 3000 Leuven, Belgium
- Correspondence: ; Tel.: +32-1634-7600; Fax: +32-1634-7623
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21
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Seitz HK, Neuman MG. The History of Alcoholic Liver Disease: From an Unrecognized Disease to One of the Most Frequent Diseases in Hepatology. J Clin Med 2021; 10:858. [PMID: 33669694 PMCID: PMC7921942 DOI: 10.3390/jcm10040858] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/10/2021] [Accepted: 02/13/2021] [Indexed: 02/06/2023] Open
Abstract
This review describes the history of alcoholic liver disease from the beginning of the 1950s until now. It details how the hepatotoxicity of alcohol was discovered by epidemiology and basic research primarily by using new feeding techniques in rodents and primates. The article also recognizes the pioneering work of scientists who contributed to the understanding of the pathophysiology of alcoholic liver disease. In addition, clinical aspects, such as the development of diagnostics and treatment options for alcoholic liver disease, are discussed. Up-to-date knowledge of the mechanism of the disease in 2020 is presented.
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Affiliation(s)
- Helmut K. Seitz
- Centre of Liver and Alcohol Diseases, Ethianum Clinic, 69115 Heidelberg, Germany
- Faculty of Medicine, University of Heidelberg, 69117 Heidelberg, Germany
| | - Manuela G. Neuman
- In Vitro Drug Safety and Biotechnology and the Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L5, Canada;
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22
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Hakkola J, Hukkanen J, Turpeinen M, Pelkonen O. Inhibition and induction of CYP enzymes in humans: an update. Arch Toxicol 2020; 94:3671-3722. [PMID: 33111191 PMCID: PMC7603454 DOI: 10.1007/s00204-020-02936-7] [Citation(s) in RCA: 208] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 10/12/2020] [Indexed: 12/17/2022]
Abstract
The cytochrome P450 (CYP) enzyme family is the most important enzyme system catalyzing the phase 1 metabolism of pharmaceuticals and other xenobiotics such as herbal remedies and toxic compounds in the environment. The inhibition and induction of CYPs are major mechanisms causing pharmacokinetic drug–drug interactions. This review presents a comprehensive update on the inhibitors and inducers of the specific CYP enzymes in humans. The focus is on the more recent human in vitro and in vivo findings since the publication of our previous review on this topic in 2008. In addition to the general presentation of inhibitory drugs and inducers of human CYP enzymes by drugs, herbal remedies, and toxic compounds, an in-depth view on tyrosine-kinase inhibitors and antiretroviral HIV medications as victims and perpetrators of drug–drug interactions is provided as examples of the current trends in the field. Also, a concise overview of the mechanisms of CYP induction is presented to aid the understanding of the induction phenomena.
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Affiliation(s)
- Jukka Hakkola
- Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, POB 5000, 90014, Oulu, Finland.,Biocenter Oulu, University of Oulu, Oulu, Finland.,Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Janne Hukkanen
- Biocenter Oulu, University of Oulu, Oulu, Finland.,Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Miia Turpeinen
- Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, POB 5000, 90014, Oulu, Finland.,Administration Center, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Olavi Pelkonen
- Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, POB 5000, 90014, Oulu, Finland.
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23
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Seitz HK. The role of cytochrome P4502E1 in the pathogenesis of alcoholic liver disease and carcinogenesis. Chem Biol Interact 2019; 316:108918. [PMID: 31836462 DOI: 10.1016/j.cbi.2019.108918] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 11/26/2019] [Accepted: 12/10/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Helmut K Seitz
- Centre of Alcohol Research (CAR), University of Heidelberg, Heidelberg and Department of Medicine, Salem Medical Centre, Heidelberg, Germany.
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24
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Song BJ, Abdelmegeed MA, Cho YE, Akbar M, Rhim JS, Song MK, Hardwick JP. Contributing Roles of CYP2E1 and Other Cytochrome P450 Isoforms in Alcohol-Related Tissue Injury and Carcinogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1164:73-87. [PMID: 31576541 DOI: 10.1007/978-3-030-22254-3_6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The purpose of this review is to briefly summarize the roles of alcohol (ethanol) and related compounds in promoting cancer and inflammatory injury in many tissues. Long-term chronic heavy alcohol exposure is known to increase the chances of inflammation, oxidative DNA damage, and cancer development in many organs. The rates of alcohol-mediated organ damage and cancer risks are significantly elevated in the presence of co-morbidity factors such as poor nutrition, unhealthy diets, smoking, infection with bacteria or viruses, and exposure to pro-carcinogens. Chronic ingestion of alcohol and its metabolite acetaldehyde may initiate and/or promote the development of cancer in the liver, oral cavity, esophagus, stomach, gastrointestinal tract, pancreas, prostate, and female breast. In this chapter, we summarize the important roles of ethanol/acetaldehyde in promoting inflammatory injury and carcinogenesis in several tissues. We also review the updated roles of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) and other cytochrome P450 isozymes in the metabolism of various potentially toxic substrates, and consequent toxicities, including carcinogenesis in different tissues. We also briefly describe the potential implications of endogenous ethanol produced by gut bacteria, as frequently observed in the experimental models and patients of nonalcoholic fatty liver disease, in promoting DNA mutation and cancer development in the liver and other tissues, including the gastrointestinal tract.
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Affiliation(s)
- Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
| | - Mohamed A Abdelmegeed
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA
| | - Young-Eun Cho
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.,Department of Food Science and Nutrition, Andong National University, Andong, Republic of Korea
| | - Mohammed Akbar
- Division of Neuroscience and Behavior, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA
| | - Johng S Rhim
- Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Min-Kyung Song
- Investigational Drug Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - James P Hardwick
- Biochemistry and Molecular Pathology in the Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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25
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Hohmann N, Blank A, Burhenne J, Suzuki Y, Mikus G, Haefeli WE. Simultaneous phenotyping of CYP2E1 and CYP3A using oral chlorzoxazone and midazolam microdoses. Br J Clin Pharmacol 2019; 85:2310-2320. [PMID: 31222796 PMCID: PMC6783597 DOI: 10.1111/bcp.14040] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 05/31/2019] [Accepted: 06/10/2019] [Indexed: 12/24/2022] Open
Abstract
AIMS Chlorzoxazone is the paradigm marker substrate for CYP2E1 phenotyping in vivo. Because at the commonly used milligram doses (250-750 mg) chlorzoxazone acts as an inhibitor of the CYP3A4/5 marker substrate midazolam, previous attempts failed to combine both drugs in a common phenotyping cocktail. Microdosing chlorzoxazone could circumvent this problem. METHOD We enrolled 12 healthy volunteers in a trial investigating the dose-exposure relationship of single ascending chlorzoxazone oral doses over a 10,000-fold range (0.05-500 mg) and assessed the effect of 0.1 and 500 mg of chlorzoxazone on oral midazolam pharmacokinetics (0.003 mg). RESULTS Chlorzoxazone area under the concentration-time curve was dose-linear in the dose range between 0.05 and 5 mg. A nonlinear increase occurred with doses ≥50 mg, probably due to saturated presystemic metabolic elimination. While midazolam area under the concentration-time curve increased 2-fold when coadministered with 500 mg of chlorzoxazone, there was no pharmacokinetic interaction between chlorzoxazone and midazolam microdoses. CONCLUSION The chlorzoxazone microdose did not interact with the CYP3A marker substrate midazolam, enabling the simultaneous administration in a phenotyping cocktail. This microdose assay is now ready to be further validated and tested as a phenotyping procedure assessing the impact of induction and inhibition of CYP2E1 on chlorzoxazone microdose pharmacokinetics.
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Affiliation(s)
- Nicolas Hohmann
- Present address:
Department of Clinical Pharmacology and PharmacoepidemiologyUniversity Hospital HeidelbergGermany
| | - Antje Blank
- Present address:
Department of Clinical Pharmacology and PharmacoepidemiologyUniversity Hospital HeidelbergGermany
| | - Jürgen Burhenne
- Present address:
Department of Clinical Pharmacology and PharmacoepidemiologyUniversity Hospital HeidelbergGermany
| | - Yosuke Suzuki
- Present address:
Department of Clinical Pharmacology and PharmacoepidemiologyUniversity Hospital HeidelbergGermany
| | - Gerd Mikus
- Present address:
Department of Clinical Pharmacology and PharmacoepidemiologyUniversity Hospital HeidelbergGermany
| | - Walter E. Haefeli
- Present address:
Department of Clinical Pharmacology and PharmacoepidemiologyUniversity Hospital HeidelbergGermany
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26
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Godoy FR, Nunes HF, Alves AA, Carvalho WF, Franco FC, Pereira RR, da Cruz AS, da Silva CC, Bastos RP, de Melo E Silva D. Increased DNA damage is not associated to polymorphisms in OGGI DNA repair gene, CYP2E1 detoxification gene, and biochemical and hematological findings in soybeans farmers from Central Brazil. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2019; 26:26553-26562. [PMID: 31292876 DOI: 10.1007/s11356-019-05882-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 07/01/2019] [Indexed: 06/09/2023]
Abstract
Our study evaluated 163 individuals, being 74 soybean farmers, occupationally exposed to pesticides, and 89 individuals from Goias municipalities, Central Brazil, with similar conditions to the exposed group, comprising the control group. Of the 74 soybean farmers, 43 exposed directly to pesticides and 31 exposed indirectly. The exposed group consisted of individuals aged 19 to 63 years, 21 women and 53 men, and the control group had ages ranging from 18 to 64 years, being 36 women and 53 men. 18.9% of the exposed group were poisoned by pesticides, and the most common symptoms were headache and gastrointestinal problems. The genotype frequencies of the rs2031920 (T>C) polymorphism in the CYP2E1 gene present significant differences between the exposed and control groups (p = 0.02), showing that 24.3% of the exposed group were heterozygotes against 6.7% in the control group. For the OGG1 gene, two SNPs, rs1052133 (G>C) and rs293795 (T>C), were evaluated and the genotype frequencies were not statistically different between the exposed and control groups. The DNA damage was distinct (p < 0.05) in the three analyzed comet parameters (tail length, Olive tail moment, %DNA) between groups. However, there was no influence of age and alcohol consumption between the groups associated with the polymorphisms in the CYP2E1 and OGG1 genes and DNA damage. We also did not find altered hematological and biochemical parameters in the exposed group. Thus, this pioneering study at Goias State carried out an overview of the health of soybean farmers. We evaluated classic laboratory exams, associated with exposure markers (comet assay) and susceptibility markers (genetic polymorphisms), emphasizing the need to expand the Brazilian health assessment protocol. We found, in soybean farmers, increased DNA damage and a higher number of heterozygotes in CYP2E1 gene, compared with the control group, despite the lack of association with age, educational level, smoking, drinking habits, and genetic polymorphisms.
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Affiliation(s)
- Fernanda Ribeiro Godoy
- Laboratório de Mutagênese, Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Hugo Freire Nunes
- Laboratório de Mutagênese, Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Alessandro Arruda Alves
- Laboratório de Mutagênese, Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Wanessa Fernandes Carvalho
- Laboratório de Mutagênese, Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Fernanda Craveiro Franco
- Laboratório de Virologia Animal, Instituto de Patologia Tropical, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Rodrigo Roncato Pereira
- Laboratório de Mutagênese, Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Alex Silva da Cruz
- Escola de Ciências Biológicas e Agrárias, Campus II, Núcleo de Pesquisas Replicon, Pontifícia Universidade Católica de Goiás, Goiânia, Goiás, Brazil
| | - Cláudio Carlos da Silva
- Escola de Ciências Biológicas e Agrárias, Campus II, Núcleo de Pesquisas Replicon, Pontifícia Universidade Católica de Goiás, Goiânia, Goiás, Brazil
| | - Rogério Pereira Bastos
- Laboratório de Herpetologia e Comportamento Animal, Programa de Pós-Graduação em Biodiversidade Animal, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Daniela de Melo E Silva
- Laboratório de Mutagênese, Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal de Goiás, Goiânia, Goiás, Brazil.
- Depto. de Genética, Instituto de Ciências Biológicas, ICB I, Universidade Federal de Goiás, Bairro: Campus Universitário, Goiânia, GO, CEP: 74690-900, Brazil.
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27
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Matsushita H, Takaki A. Alcohol and hepatocellular carcinoma. BMJ Open Gastroenterol 2019; 6:e000260. [PMID: 31139422 PMCID: PMC6505979 DOI: 10.1136/bmjgast-2018-000260] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 01/04/2019] [Accepted: 01/12/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Alcohol is classified as a Group 1 carcinogen by the International Agency for Research on Cancer because it induces hepatocellular carcinoma (among other cancers) in humans. An excessive alcohol intake may result in fatty liver, acute/chronic hepatitis, and cirrhosis and eventually lead to hepatocellular carcinoma. It has been reported that alcohol abuse increases the relative risk of hepatocellular carcinoma by 3- to 10-fold. AIM AND METHODS To clarify the known mechanisms of alcohol-related carcinogenesis, we searched Pubmed using the terms alcohol and immune mechanism, alcohol and cancer, and immune mechanism and cancer and summarized the articles as a qualitative review. RESULTS From a clinical perspective, it is well known that alcohol interacts with other factors, such as smoking, viral hepatitis, and diabetes, leading to an increased risk of hepatocellular carcinoma. There are several possible mechanisms through which alcohol may induce liver carcinogenicity, including the mutagenic effects of acetaldehyde and the production of ROS due to the excessive hepatic deposition of iron. Furthermore, it has been reported that alcohol accelerates hepatitis C virus-induced liver tumorigenesis through TLR4 signaling. Despite intense investigations to elucidate the mechanisms, they remain poorly understood. CONCLUSION This review summarizes the recent findings of clinical and pathological studies that have investigated the carcinogenic effects of alcohol in the liver.
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Affiliation(s)
- Hiroshi Matsushita
- Department of Gastroenterology and Hepatology, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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28
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Gade C, Dalhoff K, Petersen T, Riis T, Schmeltz C, Chabanova E, Christensen HR, Mikus G, Burhenne J, Holm JC, Holst H. Obesity-induced CYP2E1 activity in children. Br J Clin Pharmacol 2018; 85:458-459. [PMID: 30537026 DOI: 10.1111/bcp.13813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/01/2018] [Accepted: 11/03/2018] [Indexed: 11/27/2022] Open
Affiliation(s)
- Christina Gade
- Department of Clinical Pharmacology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark
| | - Kim Dalhoff
- Department of Clinical Pharmacology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark
| | - Tonny Petersen
- Department of Clinical Pharmacology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark
| | - Troels Riis
- Department of Clinical Pharmacology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark
| | - Camilla Schmeltz
- The Children's Obesity Clinic, Department of Paediatrics, Copenhagen University Hospital Holbaek, Denmark
| | - Elizaveta Chabanova
- Department of Radiology, Copenhagen University Hospital, Herlev and Gentofte, Denmark
| | - Hanne Rolighed Christensen
- Department of Clinical Pharmacology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark
| | - Gerd Mikus
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Germany
| | - Juergen Burhenne
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Germany
| | - Jens Christian Holm
- The Children's Obesity Clinic, Department of Paediatrics, Copenhagen University Hospital Holbaek, Denmark.,Novo Nordisk Foundation Centre for Basic Metabolic Research, Denmark
| | - Helle Holst
- Department of Clinical Pharmacology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark
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29
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Kaur H, Sarma P, Prakash A, Medhi B. CYP2E1 activity and children with obesity: possible confounding factors. Br J Clin Pharmacol 2018; 85:457. [PMID: 30334271 DOI: 10.1111/bcp.13769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 08/25/2018] [Accepted: 09/06/2018] [Indexed: 02/05/2023] Open
Abstract
Lots of factors can influence CYP2E1 activities, e.g. thyroid status, different types of anaemia (fanconi anaemia and sideroblastic anaemia), etc. Alcohol is a known inducer of CYP2E1, therefore a justifiable duration of abstinence is required before the subjects are enrolled into a study for normalization of CYP2E1 activity. In this letter we address these confounding factors and their role in CYP2E1 activity.
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Affiliation(s)
- Hardeep Kaur
- Department of Pharmacology, PGIMER, Chandigarh, India
| | - Phulen Sarma
- Department of Pharmacology, PGIMER, Chandigarh, India
| | - Ajay Prakash
- Department of Pharmacology, PGIMER, Chandigarh, India
| | - Bikash Medhi
- Department of Pharmacology, PGIMER, Chandigarh, India
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30
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Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, Mathurin P, Mueller S, Szabo G, Tsukamoto H. Alcoholic liver disease. Nat Rev Dis Primers 2018; 4:16. [PMID: 30115921 DOI: 10.1038/s41572-018-0014-7] [Citation(s) in RCA: 786] [Impact Index Per Article: 112.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease worldwide. ALD can progress from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which is characterized by hepatic inflammation. Chronic ASH can eventually lead to fibrosis and cirrhosis and in some cases hepatocellular cancer (HCC). In addition, severe ASH (with or without cirrhosis) can lead to alcoholic hepatitis, which is an acute clinical presentation of ALD that is associated with liver failure and high mortality. Most individuals consuming >40 g of alcohol per day develop AFL; however, only a subset of individuals will develop more advanced disease. Genetic, epigenetic and non-genetic factors might explain the considerable interindividual variation in ALD phenotype. The pathogenesis of ALD includes hepatic steatosis, oxidative stress, acetaldehyde-mediated toxicity and cytokine and chemokine-induced inflammation. Diagnosis of ALD involves assessing patients for alcohol use disorder and signs of advanced liver disease. The degree of AFL and liver fibrosis can be determined by ultrasonography, transient elastography, MRI, measurement of serum biomarkers and liver biopsy histology. Alcohol abstinence achieved by psychosomatic intervention is the best treatment for all stages of ALD. In the case of advanced disease such as cirrhosis or HCC, liver transplantation may be required. Thus, new therapies are urgently needed.
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Affiliation(s)
- Helmut K Seitz
- Centre of Alcohol Research (CAR),, University of Heidelberg, Heidelberg and Department of Medicine, Salem Medical Center, Heidelberg, Germany.
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Helena Cortez-Pinto
- Departmento de Gastroenterologia, CHLN, Laboratorio de Nutricão, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA
| | - Antoni Gual
- Addiction Unit, Neuroscience Institute Hospital Clinic, IDIBAPS, Barcelona, Spain
| | - Carolin Lackner
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Philippe Mathurin
- Service des Maladies de l'Appareil Digestif, Universite Lille 2 and INSERM U795, Lille, France
| | - Sebastian Mueller
- Centre of Alcohol Research (CAR),, University of Heidelberg, Heidelberg and Department of Medicine, Salem Medical Center, Heidelberg, Germany
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Hidekazu Tsukamoto
- University of Southern California Keck School of Medicine and Greater Los Angeles VA Healthcare System, Los Angeles, CA, USA
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31
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Gazzaz M, Kinzig M, Schaeffeler E, Jübner M, Hsin CH, Li X, Taubert M, Trueck C, Iltgen-Breburda J, Kraus D, Queckenberg C, Stoffel M, Schwab M, Sörgel F, Fuhr U. Drinking Ethanol Has Few Acute Effects on CYP2C9, CYP2C19, NAT2, and P-Glycoprotein Activities but Somewhat Inhibits CYP1A2, CYP2D6, and Intestinal CYP3A: So What? Clin Pharmacol Ther 2018; 104:1249-1259. [DOI: 10.1002/cpt.1083] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 03/02/2018] [Accepted: 03/29/2018] [Indexed: 11/11/2022]
Affiliation(s)
- Malaz Gazzaz
- Department I of Pharmacology; University Hospital Cologne; Germany
- Department of Clinical Pharmacy, College of Pharmacy; Umm Al-Qura University; Makkah Saudi Arabia
| | - Martina Kinzig
- Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg; Germany
| | - Elke Schaeffeler
- Dr. Margarete-Fischer-Bosch Institute of Clinical Pharmacology; Stuttgart Germany
- University of Tuebingen; Tuebingen Germany
| | - Martin Jübner
- Institute of Legal Medicine, Faculty of Medicine; University of Cologne; Germany
| | - Chih-hsuan Hsin
- Department I of Pharmacology; University Hospital Cologne; Germany
| | - Xia Li
- Department I of Pharmacology; University Hospital Cologne; Germany
| | - Max Taubert
- Department I of Pharmacology; University Hospital Cologne; Germany
| | - Christina Trueck
- Department I of Pharmacology; University Hospital Cologne; Germany
| | | | - Daria Kraus
- Department I of Pharmacology; University Hospital Cologne; Germany
- Clinical Trials Centre; University Hospital Cologne; Germany
| | - Christian Queckenberg
- Department I of Pharmacology; University Hospital Cologne; Germany
- Clinical Trials Centre; University Hospital Cologne; Germany
| | - Marc Stoffel
- Department I of Pharmacology; University Hospital Cologne; Germany
| | - Matthias Schwab
- Dr. Margarete-Fischer-Bosch Institute of Clinical Pharmacology; Stuttgart Germany
- Department of Clinical Pharmacology; University Hospital Tuebingen; Germany
- Department of Pharmacy and Biochemistry; University of Tuebingen; Tuebingen Germany
| | - Fritz Sörgel
- Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg; Germany
- Institute of Pharmacology; Faculty of Medicine, University Duisburg-Essen; Essen Germany
| | - Uwe Fuhr
- Department I of Pharmacology; University Hospital Cologne; Germany
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Stornetta A, Guidolin V, Balbo S. Alcohol-Derived Acetaldehyde Exposure in the Oral Cavity. Cancers (Basel) 2018; 10:E20. [PMID: 29342885 PMCID: PMC5789370 DOI: 10.3390/cancers10010020] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 01/09/2018] [Accepted: 01/10/2018] [Indexed: 12/12/2022] Open
Abstract
Alcohol is classified by the International Agency for Research on Cancer (IARC) as a human carcinogen and its consumption has been associated to an increased risk of liver, breast, colorectum, and upper aerodigestive tract (UADT) cancers. Its mechanisms of carcinogenicity remain unclear and various hypotheses have been formulated depending on the target organ considered. In the case of UADT cancers, alcohol's major metabolite acetaldehyde seems to play a crucial role. Acetaldehyde reacts with DNA inducing modifications, which, if not repaired, can result in mutations and lead to cancer development. Despite alcohol being mainly metabolized in the liver, several studies performed in humans found higher levels of acetaldehyde in saliva compared to those found in blood immediately after alcohol consumption. These results suggest that alcohol-derived acetaldehyde exposure may occur in the oral cavity independently from liver metabolism. This hypothesis is supported by our recent results showing the presence of acetaldehyde-related DNA modifications in oral cells of monkeys and humans exposed to alcohol, overall suggesting that the alcohol metabolism in the oral cavity is an independent cancer risk factor. This review article will focus on illustrating the factors modulating alcohol-derived acetaldehyde exposure and effects in the oral cavity.
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Affiliation(s)
- Alessia Stornetta
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
| | - Valeria Guidolin
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
- Division of Environmental Health Sciences, University of Minnesota, Minneapolis, MN 55455, USA.
| | - Silvia Balbo
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
- Division of Environmental Health Sciences, University of Minnesota, Minneapolis, MN 55455, USA.
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Chronic Ethanol Consumption and Generation of Etheno-DNA Adducts in Cancer-Prone Tissues. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1032:81-92. [PMID: 30362092 DOI: 10.1007/978-3-319-98788-0_6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chronic ethanol consumption is a risk factor for several human cancers. A variety of mechanisms may contribute to this carcinogenic effect of alcohol including oxidative stress with the generation of reactive oxygen species (ROS), formed via inflammatory pathways or as byproducts of ethanol oxidation through cytochrome P4502E1 (CYP2E1). ROS may lead to lipidperoxidation (LPO) resulting in LPO-products such as 4-hydoxynonenal (4-HNE) or malondialdehyde. These compounds can react with DNA bases forming mutagenic and carcinogenic etheno-DNA adducts. Etheno-DNA adducts are generated in the liver (HepG2) cells over-expressing CYP2E1 when incubated with ethanol;and are inhibited by chlormethiazole. In liver biopsies etheno-DNA adducts correlated significantly with CYP2E1. Such a correlation was also found in the esophageal- and colorectal mucosa of alcoholics. Etheno-DNA adducts also increased in liver biopsies from patients with non alcoholic steatohepatitis (NASH). In various animal models with fatty liver either induced by high fat diets or genetically modified such as in the obese Zucker rat, CYP2E1 is induced and paralleled by high levels of etheno DNA-adducts which may be modified by additional alcohol administration. As elevation of adduct levels in NASH children were already detected at a young age, these lesions may contribute to hepatocellular cancer development later in life. Together these data strongly implicate CYP2E1 as an important mediator for etheno-DNA adduct formation, and this detrimental DNA damage may act as a driving force for malignant disease progression.
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Mueller S, Peccerella T, Qin H, Glassen K, Waldherr R, Flechtenmacher C, Straub BK, Millonig G, Stickel F, Bruckner T, Bartsch H, Seitz HK. Carcinogenic Etheno DNA Adducts in Alcoholic Liver Disease: Correlation with Cytochrome P-4502E1 and Fibrosis. Alcohol Clin Exp Res 2017; 42:252-259. [PMID: 29120493 DOI: 10.1111/acer.13546] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 11/01/2017] [Indexed: 12/26/2022]
Abstract
BACKGROUND One mechanism by which alcoholic liver disease (ALD) progresses is oxidative stress and the generation of reactive oxygen species, among others due to the induction of cytochrome P-4502E1 (CYP2E1). Experimental data underline the key role of CYP2E1 because ALD could be partially prevented in rats by the administration of the specific CYP2E1 inhibitor chlormethiazole. As CYP2E1 is linked to the formation of carcinogenic etheno DNA adducts in ALD patients, a causal role of alcohol-induced CYP2E1 in hepatocarcinogenesis is implicated. The purpose of this study was to investigate CYP2E1 induction in ALD, and its correlation with oxidative DNA lesions and with hepatic histology. METHODS Hepatic biopsies from 97 patients diagnosed with ALD were histologically scored for steatosis, inflammation, and fibrosis. CYP2E1 and the exocyclic etheno DNA adduct 1,N6 -etheno-2'deoxyadenosine (εdA) were determined immunohistochemically. In addition, in 42 patients, 8-hydroxydeoxyguanosine (8-OHdG) was also evaluated using immunohistochemistry. RESULTS A significant positive correlation was found between CYP2E1 and εdA (p < 0.0001) as well as between CYP2E1 and 8-OHdG (p = 0.039). Both CYP2E1 (p = 0.0094) and ɛdA (p < 0.0001) also correlated significantly with the stage of hepatic fibrosis. Furthermore, a significant correlation between the fibrosis stage and the grade of lobular inflammation (p < 0.0001) was observed. However, the amount of alcohol consumed did not correlate with any of the parameters determined. CONCLUSIONS These data suggest an important role of CYP2E1 in the generation of εdA, in the fibrotic progression of ALD, and thus in alcohol-mediated hepatocarcinogenesis. CYP2E1 may be a target in the treatment of ALD and a potential prognostic marker for disease progression.
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Affiliation(s)
- Sebastian Mueller
- Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany.,Department of Medicine (Gastroenterology & Hepatology), Salem Medical Centre, Heidelberg, Germany
| | - Teresa Peccerella
- Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany
| | - Hua Qin
- Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany
| | - Katharina Glassen
- Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany
| | - Rüdiger Waldherr
- Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany
| | | | - Beate K Straub
- Department of Pathology, University of Heidelberg, Heidelberg, Germany.,Institute of Pathology, University Medicine, University of Mainz, Mainz, Germany
| | - Gunda Millonig
- Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Thomas Bruckner
- Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Helmut Bartsch
- Division of Toxicology and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Helmut Karl Seitz
- Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany.,Department of Medicine (Gastroenterology & Hepatology), Salem Medical Centre, Heidelberg, Germany
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Alcohol, smoking and the liver disease patient. Best Pract Res Clin Gastroenterol 2017; 31:537-543. [PMID: 29195673 DOI: 10.1016/j.bpg.2017.09.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 08/31/2017] [Accepted: 09/03/2017] [Indexed: 02/06/2023]
Abstract
Alcohol is an established risk factor for cirrhosis. Current recommendations for a "safe" limit for alcohol consumption are usually set to around 30 g of alcohol per day for men and 20 g per day for women, but evidence is mounting that these cut-offs might be set too high. Also, inter-individual differences in the hepatic sensitivity for alcohol likely play into the risk of development of cirrhosis. In patients with concomitant liver diseases, a synergistic effect on fibrosis progression and high consumption of alcohol is evident. The role of low to moderate consumption is less clear. Alcohol can also lead to a specific inflammatory state in the liver, alcoholic hepatitis (AH). Treatment of severe AH consists of corticosteroids, which are at best moderately effective, and new treatments are needed. Liver transplantation is an option in severe alcoholic liver disease, although selection of patients that are at a very low risk of post-transplantation alcohol consumption is paramount. There is some evidence to suggest an increased risk for fibrosis progression and development of hepatocellular carcinoma specifically for smoking.
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Stickel F, Datz C, Hampe J, Bataller R. Pathophysiology and Management of Alcoholic Liver Disease: Update 2016. Gut Liver 2017; 11:173-188. [PMID: 28274107 PMCID: PMC5347641 DOI: 10.5009/gnl16477] [Citation(s) in RCA: 162] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 10/14/2016] [Indexed: 12/13/2022] Open
Abstract
Alcoholic liver disease (ALD) is a leading cause of cirrhosis, liver cancer, and acute and chronic liver failure and as such causes significant morbidity and mortality. While alcohol consumption is slightly decreasing in several European countries, it is rising in others and remains high in many countries around the world. The pathophysiology of ALD is still incompletely understood but relates largely to the direct toxic effects of alcohol and its main intermediate, acetaldehyde. Recently, novel putative mechanisms have been identified in systematic scans covering the entire human genome and raise new hypotheses on previously unknown pathways. The latter also identify host genetic risk factors for significant liver injury, which may help design prognostic risk scores. The diagnosis of ALD is relatively easy with a panel of well-evaluated tests and only rarely requires a liver biopsy. Treatment of ALD is difficult and grounded in abstinence as the pivotal therapeutic goal; once cirrhosis is established, treatment largely resembles that of other etiologies of advanced liver damage. Liver transplantation is a sound option for carefully selected patients with cirrhosis and alcoholic hepatitis because relapse rates are low and prognosis is comparable to other etiologies. Still, many countries are restrictive in allocating donor livers for ALD patients. Overall, few therapeutic options exist for severe ALD. However, there is good evidence of benefit for only corticosteroids in severe alcoholic hepatitis, while most other efforts are of limited efficacy. Considering the immense burden of ALD worldwide, efforts of medical professionals and industry partners to develop targeted therapies in ALF has been disappointingly low.
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Affiliation(s)
- Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich,
Switzerland
| | - Christian Datz
- Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf,
Austria
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, TU Dresden, Dresden,
Germany
| | - Ramon Bataller
- Division of Gastroenterology and Hepatology, Department of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC,
USA
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37
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Jones AW. Impact of Trauma, Massive Blood Loss and Administration of Resuscitation Fluids on a Person's Blood-Alcohol Concentration and Rate of Ethanol Metabolism. Acad Forensic Pathol 2016; 6:77-88. [PMID: 31239874 DOI: 10.23907/2016.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 10/30/2015] [Accepted: 12/05/2015] [Indexed: 11/12/2022]
Abstract
Excessive drinking and drunkenness are tightly linked to many types of intentional and unintentional injuries involving trauma and blood loss, which often necessitate emergency medical intervention. This article considers the impact of trauma, massive blood loss, and the administration of life-saving replacement fluids on a person's blood alcohol concentration (BAC) and rate of ethanol metabolism. Both German and English language journals were reviewed and results from animal experiments, human studies, and actual victims of trauma undergoing life-saving treatment were considered. If trauma-related bleeding occurs when some ingested alcohol remains unabsorbed in the stomach, then under these circumstances continued absorption into portal venous blood is delayed, owing to altered splanchnic circulation. Hemodilution caused by administration of replacement fluids has only minimal effects on a preexisting BAC, because ethanol distributes into the total body water (TBW) compartment, which represents 50-60% of body weight. After hypovolemia there is a transfer of fluids from tissue compartments into the blood, which becomes more like plasma in composition with lower hematocrit and hemoglobin content. Unless the trauma or emergency treatment impedes hepatic blood flow, the rate of ethanol metabolism is not expected to differ from normal values, namely 0.10-0.25 g/L/h (0.01-0.025 g% per h). If ethanol is fully absorbed and distributed in all body fluids and tissues, neither massive blood loss nor administration of resuscitating fluids is expected to have any significant effect on a preexisting BAC or the rate of ethanol metabolism.
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Affiliation(s)
- Alan W Jones
- Department of Clinical Pharmacology, Faculty of Medicine, University of Linköping, Sweden
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38
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Hayward KL, Powell EE, Irvine KM, Martin JH. Can paracetamol (acetaminophen) be administered to patients with liver impairment? Br J Clin Pharmacol 2016; 81:210-22. [PMID: 26460177 PMCID: PMC4833155 DOI: 10.1111/bcp.12802] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 10/09/2015] [Accepted: 10/09/2015] [Indexed: 12/15/2022] Open
Abstract
Although 60 years have passed since it became widely available on the therapeutic market, paracetamol dosage in patients with liver disease remains a controversial subject. Fulminant hepatic failure has been a well documented consequence of paracetamol overdose since its introduction, while short and long term use have both been associated with elevation of liver transaminases, a surrogate marker for acute liver injury. From these reports it has been assumed that paracetamol use should be restricted or the dosage reduced in patients with chronic liver disease. We review the factors that have been purported to increase risk of hepatocellular injury from paracetamol and the pharmacokinetic alterations in different pathologies of chronic liver disease which may affect this risk. We postulate that inadvertent under-dosing may result in concentrations too low to enable efficacy. Specific research to improve the evidence base for prescribing paracetamol in patients with different aetiologies of chronic liver disease is needed.
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Affiliation(s)
- Kelly L. Hayward
- Pharmacy DepartmentPrincess Alexandra HospitalQueensland
- Centre for Liver Disease ResearchThe University of QueenslandQueensland
| | - Elizabeth E. Powell
- Centre for Liver Disease ResearchThe University of QueenslandQueensland
- Department of Gastroenterology and HepatologyPrincess Alexandra HospitalQueensland
| | | | - Jennifer H. Martin
- School of Medicine and Public HealthUniversity of NewcastleNew South Wales
- The University of Queensland Diamantina InstituteQueenslandAustralia
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McKillop IH, Schrum LW, Thompson KJ. Role of alcohol in the development and progression of hepatocellular carcinoma. Hepat Oncol 2016; 3:29-43. [PMID: 30191025 PMCID: PMC6095421 DOI: 10.2217/hep.15.40] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 10/22/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant cause of cancer-related morbidity and mortality. Chronic, heavy ethanol consumption is a major risk for developing the worsening liver pathologies that culminate in hepatic cirrhosis, the leading risk factor for developing HCC. A significant body of work reports the biochemical and pathological consequences of ethanol consumption and metabolism during hepatocarcinogeneis. The systemic effects of ethanol means organ system interactions are equally important in understanding the initiation and progression of HCC within the alcoholic liver. This review aims to summarize the effects of ethanol-ethanol metabolism during the pathogenesis of alcoholic liver disease, the progression toward HCC and the importance of ethanol as a comorbid factor for HCC development.
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Affiliation(s)
- Iain H McKillop
- Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203 USA
| | - Laura W Schrum
- Department of Medicine, Carolinas Medical Center, Charlotte, NC 28203 USA
| | - Kyle J Thompson
- Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203 USA
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40
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Cox JA, Fellows MD, Hashizume T, White PA. The utility of metabolic activation mixtures containing human hepatic post-mitochondrial supernatant (S9) for in vitro genetic toxicity assessment. Mutagenesis 2015; 31:117-30. [PMID: 26712374 DOI: 10.1093/mutage/gev082] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
In vitro genotoxicity assessment routinely employs an exogenous metabolic activation mixture to simulate mammalian metabolism. Activation mixtures commonly contain post-mitochondrial liver supernatant (i.e. S9) from chemically induced Sprague Dawley rats. Although Organization for Economic Cooperation and Development (OECD) test guidelines permit the use of other S9 preparations, assessments rarely employ human-derived S9. The objective of this study is to review and evaluate the use of human-derived S9 for in vitro genetic toxicity assessment. All available published genotoxicity assessments employing human S9 were compiled for analysis. To facilitate comparative analyses, additional matched Ames data using induced rat liver S9 were obtained for certain highly cited chemicals. Historical human and induced rat S9 quality control reports from Moltox were obtained and mined for enzyme activity and mutagenic potency data. Additional in vitro micronucleus data were experimentally generated using human and induced rat S9. The metabolic activity of induced rat S9 was found to be higher than human S9, and linked to high mutagenic potency results. This study revealed that human S9 often yields significantly lower Salmonella mutagenic potency values, especially for polycyclic aromatic hydrocarbons, aflatoxin B1 and heterocyclic amines (~3- to 350-fold). Conversely, assessment with human S9 activation yields higher potency for aromatic amines (~2- to 50-fold). Outliers with extremely high mutagenic potency results were observed in the human S9 data. Similar trends were observed in experimentally generated mammalian micronucleus cell assays, however human S9 elicited potent cytotoxicity L5178Y, CHO and TK6 cell lines. Due to the potential for reduced sensitivity and the absence of a link between enzyme activity levels and mutagenic potency, human liver S9 is not recommended for use alone in in vitro genotoxicity screening assays; however, human S9 may be extremely useful in follow-up tests, especially in the case of chemicals with species-specific metabolic differences, such as aromatic amines.
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Affiliation(s)
- Julie A Cox
- Environmental Health Science and Research Bureau, Health Canada, 50 Colombine Driveway, Tunney's Pasture 0803A, Ottawa, Ontario K1A 0K9, Canada, Department of Biology, University of Ottawa, 75 Laurier Ave E, Ottawa, Ontario K1N 6N5, Canada,
| | - Mick D Fellows
- Department of R&D, AstraZeneca, Alderley Park, Macclesfield, Cheshire CW11 3RN, UK and
| | - Tsuneo Hashizume
- Shonan Research Centre, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Paul A White
- Environmental Health Science and Research Bureau, Health Canada, 50 Colombine Driveway, Tunney's Pasture 0803A, Ottawa, Ontario K1A 0K9, Canada, Department of Biology, University of Ottawa, 75 Laurier Ave E, Ottawa, Ontario K1N 6N5, Canada,
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Gene copy number variation analysis reveals dosage-insensitive expression of CYP2E1. THE PHARMACOGENOMICS JOURNAL 2015; 16:551-558. [PMID: 26503817 DOI: 10.1038/tpj.2015.69] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 08/06/2015] [Accepted: 08/19/2015] [Indexed: 01/21/2023]
Abstract
Gene copy number variants (CNVs) of CYP2E1 have been described but not functionally characterized. Here we investigated effects of CNVs on hepatic and lymphoblastoid CYP2E1 expression. Using available single-nuleotide polymorphism microarray data and quantitative PCR, CYP2E1 gene duplication and deletion carriers were identified. CYP2E1 mRNA, protein and enzyme activity (chlorzoxazone-6-hydroxylation) phenotypes of CYP2E1 were not associated with gene copy number. Analysis of gene expression in lymphoblastoid cell lines in relation to CNV confirmed this finding in an extrahepatic tissue and for other ethnicities. Further analyses identified a linked haplotype cluster with possible influence on gene expression. In summary, our data suggest a homeostatic, gene dosage-insensitive regulation of CYP2E1 expression by unknown gene dosage compensation mechanisms. This is in striking contrast to well-known structural variations of CYP2A6 and CYP2D6 that have a strong impact on expression and activity. These findings are important in the context of pharmacogenetic prediction.
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Abstract
BACKGROUND Pain is one of the most common reasons for consulting a physician. Chronic pain patients often suffer from a variety of comorbidities, such as depression and anxiety and they are therefore often simultaneously treated with more than one drug. The probability of drug interactions increases with every additional drug. MATERIAL AND METHODS A systematic internet and literature search up to February 2015 was carried out. Systematic lists were included. In addition, the drug prescription information sheets were used and an internet search via Pubmed and google.com was carried out for drugs alone and in combination in order to find substance-specific interactions. RESULTS A differentiation is made between pharmaceutical, pharmacodynamic and pharmacokinetic drug interactions. Pharmaceutical interactions are caused by chemical, physical or physicochemical incompatibility of drugs or adjuvants used. These can even occur outside the body and during concomitant administration via the same route. A pharmacodynamic interaction in pain management is for example the additive sedative effect of opioids and benzodiazepines when taken together. Pharmacokinetic interactions occur during the absorption, distribution, metabolism and in the elimination phases. CONCLUSION Many drug interactions can be avoided by careful and continuous evaluation of pharmacotherapy and if necessary its adaptation; however, a sound knowledge of the underlying pharmacological mechanisms and the properties of currently used analgesics is necessary.
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Affiliation(s)
- K M J Syhr
- Institut für Klinische Pharmakologie, pharmazentrum frankfurt/ZAFES, Universitätsklinikum, Goethe Universität, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Deutschland
| | - B G Oertel
- Institut für Klinische Pharmakologie, pharmazentrum frankfurt/ZAFES, Universitätsklinikum, Goethe Universität, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Deutschland.,Fraunhofer-Institut für Molekularbiologie und Angewandte Oekologie - Projektgruppe Translationale Medizin und Pharmakologie (IME-TMP), Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Deutschland
| | - G Geisslinger
- Institut für Klinische Pharmakologie, pharmazentrum frankfurt/ZAFES, Universitätsklinikum, Goethe Universität, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Deutschland. .,Fraunhofer-Institut für Molekularbiologie und Angewandte Oekologie - Projektgruppe Translationale Medizin und Pharmakologie (IME-TMP), Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Deutschland.
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Seripa D, Panza F, Daragjati J, Paroni G, Pilotto A. Measuring pharmacogenetics in special groups: geriatrics. Expert Opin Drug Metab Toxicol 2015; 11:1073-88. [PMID: 25990744 DOI: 10.1517/17425255.2015.1041919] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION The cytochrome P450 (CYP) enzymes oxidize about 80% of the most commonly used drugs. Older patients form a very interesting clinical group in which an increased prevalence of adverse drug reactions (ADRs) and therapeutic failures (TFs) is observed. Might CYP drug metabolism change with age, and justify the differences in drug response observed in a geriatric setting? AREAS COVERED A complete overview of the CYP pharmacogenetics with a focus on the epigenetic CYP gene regulation by DNA methylation in the context of advancing age, in which DNA methylation might change. EXPERT OPINION Responder phenotypes consist of a continuum spanning from ADRs to TFs, with the best responders at the midpoint. CYP genetics is the basis of this continuum on which environmental and physiological factors act, modeling the phenotype observed in clinical practice. Physiological age-related changes in DNA methylation, the main epigenetic mechanisms regulating gene expression in humans, results in a physiological decrease in CYP gene expression with advancing age. This may be one of the physiological changes that, together with increased drug use, contributed to the higher prevalence of ADRs and TFs observed in the geriatric setting, thus, making geriatrics a special group for pharmacogenetics.
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Affiliation(s)
- Davide Seripa
- IRCCS Casa Sollievo della Sofferenza, Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences , San Giovanni Rotondo, Foggia , Italy
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Welcome M, Pereverzev V. Glycemic Allostasis during Mental Activities on Fasting in Non-alcohol Users and Alcohol Users with Different Durations of Abstinence. Ann Med Health Sci Res 2014; 4:S199-207. [PMID: 25364589 PMCID: PMC4212377 DOI: 10.4103/2141-9248.141959] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Glycemic allostasis is the process by which blood glucose stabilization is achieved through the balancing of glucose consumption rate and release into the blood stream under a variety of stressors. This paper reviews findings on the dynamics of glycemic levels during mental activities on fasting in non-alcohol users and alcohol users with different periods of abstinence. Referred articles for this review were searched in the databases of PubMed, Scopus, DOAJ and AJOL. The search was conducted in 2013 between January 20 and July 31. The following keywords were used in the search: alcohol action on glycemia OR brain glucose OR cognitive functions; dynamics of glycemia, dynamics of glycemia during mental activities; dynamics of glycemia on fasting; dynamics of glycemia in non-alcohol users OR alcohol users; glycemic regulation during sobriety. Analysis of the selected articles showed that glycemic allostasis during mental activities on fasting is poorly regulated in alcohol users even after a long duration of sobriety (1-4 weeks after alcohol consumption), compared to non-alcohol users. The major contributor to the maintenance of euglycemia during mental activities after the night's rest (during continuing fast) is gluconeogenesis.
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Affiliation(s)
- Mo Welcome
- Department of Normal Physiology, Belarusian State Medical University, Minsk, Belarus
| | - Va Pereverzev
- Department of Normal Physiology, Belarusian State Medical University, Minsk, Belarus
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45
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Linhart K, Bartsch H, Seitz HK. The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts. Redox Biol 2014; 3:56-62. [PMID: 25462066 PMCID: PMC4297928 DOI: 10.1016/j.redox.2014.08.009] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 08/19/2014] [Accepted: 08/25/2014] [Indexed: 12/30/2022] Open
Abstract
Exocyclic etheno-DNA adducts are mutagenic and carcinogenic and are formed by the reaction of lipidperoxidation (LPO) products such as 4-hydoxynonenal or malondialdehyde with DNA bases. LPO products are generated either via inflammation driven oxidative stress or via the induction of cytochrome P-450 2E1 (CYP2E1). In the liver CYP2E1 is induced by various compounds including free fatty acids, acetone and ethanol. Increased levels of CYP2E1 and thus, oxidative stress are observed in the liver of patients with non-alcoholic steatohepatitis (NASH) as well as in the chronic alcoholic. In addition, chronic ethanol ingestion also increases CYP2E1 in the mucosa of the oesophagus and colon. In all these tissues CYP2E1 correlates significantly with the levels of carcinogenic etheno-DNA adducts. In contrast, in patients with non-alcoholic steatohepatitis (NASH) hepatic etheno-DNA adducts do not correlate with CYP2E1 indicating that in NASH etheno-DNA adducts formation is predominately driven by inflammation rather than by CYP2E1 induction. Since etheno-DNA adducts are strong mutagens producing various types of base pair substitution mutations as well as other types of genetic damage, it is strongly believed that they are involved in ethanol mediated carcinogenesis primarily driven by the induction of CYP2E1.
Cytochrome P-450 2E1 is induced following chronic ethanol ingestion. CYP2E1 correlates with carcinogenic etheno-DNA formation. CYP2E1 and oxidative stress are important mechanisms in alcohol mediated carcinogenesis in the liver, undefined and colon. In NASH hepatic etheno-DNA adducts occur but possible due to inflammation.
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Affiliation(s)
- Kirsten Linhart
- Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany
| | - Helmut Bartsch
- Department of Medicine (Gastroenterology & Hepatology), Salem Medical Centre, Heidelberg, Germany
| | - Helmut K Seitz
- Division of Toxicology and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
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46
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Linhart K, Bartsch H, Seitz HK. The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts. Redox Biol 2014. [PMID: 25462066 DOI: 10.1016/j.redo-x.2014.08.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
Exocyclic etheno-DNA adducts are mutagenic and carcinogenic and are formed by the reaction of lipidperoxidation (LPO) products such as 4-hydoxynonenal or malondialdehyde with DNA bases. LPO products are generated either via inflammation driven oxidative stress or via the induction of cytochrome P-450 2E1 (CYP2E1). In the liver CYP2E1 is induced by various compounds including free fatty acids, acetone and ethanol. Increased levels of CYP2E1 and thus, oxidative stress are observed in the liver of patients with non-alcoholic steatohepatitis (NASH) as well as in the chronic alcoholic. In addition, chronic ethanol ingestion also increases CYP2E1 in the mucosa of the oesophagus and colon. In all these tissues CYP2E1 correlates significantly with the levels of carcinogenic etheno-DNA adducts. In contrast, in patients with non-alcoholic steatohepatitis (NASH) hepatic etheno-DNA adducts do not correlate with CYP2E1 indicating that in NASH etheno-DNA adducts formation is predominately driven by inflammation rather than by CYP2E1 induction. Since etheno-DNA adducts are strong mutagens producing various types of base pair substitution mutations as well as other types of genetic damage, it is strongly believed that they are involved in ethanol mediated carcinogenesis primarily driven by the induction of CYP2E1.
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Affiliation(s)
- Kirsten Linhart
- Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany
| | - Helmut Bartsch
- Department of Medicine (Gastroenterology & Hepatology), Salem Medical Centre, Heidelberg, Germany
| | - Helmut K Seitz
- Division of Toxicology and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
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47
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Neuman MG, Cohen L, Zakhari S, Nanau RM, Mueller S, Schneider M, Parry C, Isip R, Seitz HK. Alcoholic liver disease: a synopsis of the Charles Lieber's Memorial Symposia 2009-2012. Alcohol Alcohol 2014; 49:373-80. [PMID: 24816574 DOI: 10.1093/alcalc/agu021] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
This paper is based upon the 'Charles Lieber Satellite Symposia' organized by Manuela G. Neuman at each of the 2009-2012 Research Society on Alcoholism (RSA) Annual Meetings. The presentations represent a broad spectrum dealing with alcoholic liver disease (ALD). In addition, a literature search (2008-2013) in the discussed area was performed in order to obtain updated data. The presentations are focused on genetic polymorphisms of ethanol metabolizing enzymes and the role of cytochrome P4502E1 (CYP2E1) in ALD. In addition, alcohol-mediated hepatocarcinogenesis, immune response to alcohol and fibrogenesis in alcoholic hepatitis as well as its co-morbidities with chronic viral hepatitis infections in the presence or absence of human deficiency virus are discussed. Finally, emphasis was led on alcohol and drug interactions as well as liver transplantation for end-stage ALD.
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Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, University of Toronto, Toronto, ON, Canada Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Lawrence Cohen
- Division of Gastroenterology, Sunnybrook Health Sciences Centre, Department of Medicine, Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Samir Zakhari
- Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Radu M Nanau
- In Vitro Drug Safety and Biotechnology, University of Toronto, Toronto, ON, Canada Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Sebastian Mueller
- Centre of Alcohol Research, University of Heidelberg and Department of Medicine (Gastroenterology and Hepatology), Salem Medical Centre, Heidelberg, Germany
| | - Michelle Schneider
- Alcohol and Drug Abuse Research Unit, Medical Research Council, Stellenbosch University, Cape Town, South Africa
| | - Charles Parry
- Alcohol and Drug Abuse Research Unit, Medical Research Council, Stellenbosch University, Cape Town, South Africa Department of Psychiatry, Stellenbosch University, Cape Town, South Africa
| | - Romina Isip
- In Vitro Drug Safety and Biotechnology, University of Toronto, Toronto, ON, Canada Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Helmut K Seitz
- Centre of Alcohol Research, University of Heidelberg and Department of Medicine (Gastroenterology and Hepatology), Salem Medical Centre, Heidelberg, Germany
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48
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Hukkanen J. Induction of cytochrome P450 enzymes: a view on humanin vivofindings. Expert Rev Clin Pharmacol 2014; 5:569-85. [PMID: 23121279 DOI: 10.1586/ecp.12.39] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Janne Hukkanen
- Department of Internal Medicine, Institute of Clinical Medicine, and Biocenter Oulu, University of Oulu, Oulu, Finland.
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49
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Cuomo R, Andreozzi P, Zito FP. Alcoholic beverages and carbonated soft drinks: consumption and gastrointestinal cancer risks. Cancer Treat Res 2014; 159:97-120. [PMID: 24114477 DOI: 10.1007/978-3-642-38007-5_7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Alcoholic beverages (ABs) and carbonated soft drinks (CSDs) are widely consumed worldwide. Given the high consumption of these beverages, the scientific community has increased its focus on their health impact. There is epidemiological evidence of a causal association between AB intake and digestive cancer, but the role of alcohol in determining cancer is not fully defined. Experimental studies have so far identified multiple mechanisms involved in carcinogenesis; ethanol itself is not carcinogenic but available data suggest that acetaldehyde (AA) and reactive oxygen species-both products of ethanol metabolism-have a genotoxic effect promoting carcinogenesis. Other carcinogenetic mechanisms include nutritional deficits, changes in DNA methylation, and impaired immune surveillance. As CSDs are often suspected to cause certain gastrointestinal disorders, consequently, some researchers have hypothesized their involvement in gastrointestinal cancers. Of all the ingredients, carbon dioxide is prevalently involved in the alteration of gastrointestinal physiology by a direct mucosal effect and indirect effects mediated by the mechanical pressure determined by gas. The role of sugar or artificial sweeteners is also debated as factors involved in the carcinogenic processes. However, several surveys have failed to show any associations between CSDs and esophageal, gastric, or colon cancers. On the other hand, a slight correlation between risk of pancreatic cancer and CSD consumption has been found.
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Affiliation(s)
- Rosario Cuomo
- Department of Clinical & Experimental Medicine, Hospital School of Medicine, Federico II University, Via S. Pansini 5, Building no. 6, 80131, Naples, Italy,
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50
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Vesper HW, Sternberg MR, Frame T, Pfeiffer CM. Among 10 sociodemographic and lifestyle variables, smoking is strongly associated with biomarkers of acrylamide exposure in a representative sample of the U.S. Population. J Nutr 2013; 143:995S-1000S. [PMID: 23596166 PMCID: PMC4822994 DOI: 10.3945/jn.112.173013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Hemoglobin adducts of acrylamide (HbAA) and glycidamide (HbGA) have been measured as biomarkers of acrylamide exposure and metabolism in a nationally representative sample of the U.S. population in the NHANES 2003-2004. We assessed the association of sociodemographic (age, sex, race-ethnicity, education, and income) and lifestyle (smoking, alcohol consumption, BMI, physical activity, and dietary supplement use) variables with these biomarkers in U.S. adults (aged ≥ 20 y). We used bivariate and multiple regression models and assessed the magnitude of an estimated change in biomarker concentration with change in a covariable for 2 biomarkers of acrylamide exposure. Smoking was strongly and significantly correlated with HbAA and HbGA concentrations (rs = 0.51 and 0.42, respectively), with biomarker concentrations being 126 and 101% higher in smokers compared with nonsmokers after adjusting for sociodemographic and lifestyle covariates. Age was moderately and significantly correlated with both biomarkers (rs = -0.21 and -0.22, respectively). BMI (rs = -0.11) and alcohol consumption (rs = 0.13) were weakly yet significantly correlated with HbAA concentrations only. The estimated percentage change in biomarker concentration was ≤ 20% for all variables other than smoking after adjusting for sociodemographic and lifestyle covariates. Using multiple regression models, the sociodemographic variables explained 9 and 7% whereas the sociodemographic and lifestyle variables together explained 46 and 25% of the variability in HbAA and HbGA, respectively, showing the importance of considering and adequately controlling for these variables in future studies. Our findings will be useful in the design and analysis of future studies that assess and evaluate exposure to acrylamide and its metabolism to glycidamide.
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Affiliation(s)
| | | | | | - Christine M. Pfeiffer
- To whom correspondence should be addressed: Christine M. Pfeiffer, Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, 4770 Buford Hwy, NE, Mail Stop F55, Atlanta, GA 30341,
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