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Sastre J, Pérez S, Sabater L, Rius-Pérez S. Redox signaling in the pancreas in health and disease. Physiol Rev 2025; 105:593-650. [PMID: 39324871 DOI: 10.1152/physrev.00044.2023] [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: 12/04/2023] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024] Open
Abstract
This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.
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Affiliation(s)
- Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Hospital Clínico, Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
- Department of Cell Biology, Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia, Valencia, Spain
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2
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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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Lycopene Inhibits IL-6 Expression by Upregulating NQO1 and HO-1 via Activation of Nrf2 in Ethanol/Lipopolysaccharide-Stimulated Pancreatic Acinar Cells. Antioxidants (Basel) 2022; 11:antiox11030519. [PMID: 35326169 PMCID: PMC8944646 DOI: 10.3390/antiox11030519] [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: 02/17/2022] [Revised: 03/05/2022] [Accepted: 03/07/2022] [Indexed: 12/16/2022] Open
Abstract
In alcoholic pancreatitis, alcohol increases gut permeability, which increases the penetration of endotoxins, such as lipopolysaccharides (LPS). LPS act as clinically significant triggers to increase pancreatic damage in alcoholic pancreatitis. Ethanol or LPS treatment increases reactive oxygen species (ROS) production in pancreatic acinar cells. ROS induce inflammatory cytokine production in pancreatic acinar cells, leading to pancreatic inflammation. The nuclear erythroid-2-related factor 2 (Nrf2) pathway is activated as a cytoprotective response to oxidative stress, and induces the expression of NAD(P)H quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1). Lycopene exerts anti-inflammatory and antioxidant effects in various cells. We previously showed that lycopene inhibits NADPH oxidase to reduce ROS and IL-6 levels, and zymogene activation in ethanol or palmitoleic acid-treated pancreatic acinar cells. In this study, we examined whether lycopene inhibits IL-6 expression by activating the Nrf2/NQO1-HO-1 pathway, and reducing intracellular and mitochondrial ROS levels, in ethanol and LPS-treated pancreatic AR42J cells. Lycopene increased the phosphorylated and nuclear-translocated Nrf2 levels by decreasing the amount of Nrf2 sequestered in the cytoplasm via a complex formation with Kelch-like ECH1-associated protein 1 (Keap1). Using exogenous inhibitors targeting Nrf2 and HO-1, we showed that the upregulation of activated Nrf2 and HO-1 results in lycopene-induced suppression of IL-6 expression and ROS production. The consumption of lycopene-rich foods may prevent the development of ethanol and LPS-associated pancreatic inflammation by activating Nrf2-mediated expression of NQO1 and HO-1, thereby decreasing ROS-mediated IL-6 expression in pancreatic acinar cells.
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Srinivasan MP, Bhopale KK, Caracheo AA, Kaphalia L, Gong B, Popov VL, Boor PJ, Shakeel Ansari GA, Kaphalia BS. Exposure to binge ethanol and fatty acid ethyl esters exacerbates chronic ethanol-induced pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice. Am J Physiol Gastrointest Liver Physiol 2022; 322:G327-G345. [PMID: 34984929 PMCID: PMC8816639 DOI: 10.1152/ajpgi.00263.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Alcoholic chronic pancreatitis (ACP) is a fibroinflammatory disease of the pancreas. However, metabolic basis of ACP is not clearly understood. In this study, we evaluated differential pancreatic injury in hepatic alcohol dehydrogenase-deficient (ADH-) deer mice fed chronic ethanol (EtOH), chronic plus binge EtOH, and chronic plus binge EtOH and fatty acid ethyl esters (FAEEs, nonoxidative metabolites of EtOH) to understand the metabolic basis of ACP. Hepatic ADH- and ADH normal (ADH+) deer mice were fed Lieber-DeCarli liquid diet containing 3% (wt/vol) EtOH for 3 mo. One week before the euthanization, chronic EtOH-fed mice were further administered with an oral gavage of binge EtOH with/without FAEEs. Blood alcohol concentration (BAC), pancreatic injury, and inflammatory markers were measured. Pancreatic morphology, ultrastructural changes, and endoplasmic reticulum (ER)/oxidative stress were examined using H&E staining, electron microscopy, immunostaining, and/or Western blot, respectively. Overall, BAC was substantially increased in chronic EtOH-fed groups of ADH- versus ADH+ deer mice. A significant change in pancreatic acinar cell morphology, with mild to moderate fibrosis and ultrastructural changes evident by dilatations and disruption of ER cisternae, ER/oxidative stress along with increased levels of inflammatory markers were observed in the pancreas of chronic EtOH-fed groups of ADH- versus ADH+ deer mice. Furthermore, chronic plus binge EtOH and FAEEs exposure elevated BAC, enhanced ER/oxidative stress, and exacerbated chronic EtOH-induced pancreatic injury in ADH- deer mice suggesting a role of increased body burden of EtOH and its metabolism under reduced hepatic ADH in initiation and progression of ACP.NEW & NOTEWORTHY We established a chronic EtOH feeding model of hepatic alcohol dehydrogenase-deficient (ADH-) deer mice, which mimics several fibroinflammatory features of human alcoholic chronic pancreatitis (ACP). The fibroinflammatory and morphological features exacerbated by chronic plus binge EtOH and FAEEs exposure provide a strong case for metabolic basis of ACP. Most importantly, several pathological and molecular targets identified in this study provide a much broader understanding of the mechanism and avenues to develop therapeutics for ACP.
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Affiliation(s)
- Mukund P. Srinivasan
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Kamlesh K. Bhopale
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Anna A. Caracheo
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Lata Kaphalia
- 2Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas
| | - Bin Gong
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Vsevolod L. Popov
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Paul J. Boor
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - G. A. Shakeel Ansari
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
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Koyanagi YN, Oze I, Kasugai Y, Kawakatsu Y, Taniyama Y, Hara K, Shimizu Y, Imoto I, Ito H, Matsuo K. New insights into the genetic contribution of ALDH2 rs671 in pancreatic carcinogenesis: evaluation by mediation analysis. Cancer Sci 2022; 113:1441-1450. [PMID: 35102643 PMCID: PMC8990728 DOI: 10.1111/cas.15286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/12/2022] [Accepted: 01/23/2022] [Indexed: 11/26/2022] Open
Abstract
A functional variant on ALDH2 rs671 (G>A) confers a protective effect against alcohol‐induced carcinogenesis through an indirect pathway mediated by decreased alcohol consumption. Conversely, this variant also contributes to the accumulation of carcinogenic agents, resulting in a direct carcinogenic effect. This study aimed to separately quantify these two opposing effects of the rs671 A allele on pancreatic cancer risk and explore the impact of the rs671 A allele and alcohol consumption on pancreatic carcinogenesis. We included 426 cases and 1456 age‐ and sex‐matched controls. Odds ratio (OR) and 95% confidence interval (CI) for alcohol consumption were estimated using a conditional logistic regression model. By defining rs671 A allele and alcohol consumption as exposure and mediator, respectively, we used mediation analysis to decompose the total‐effect OR of the rs671 A allele into direct‐ and indirect‐effect ORs. Alcohol consumption (10 g/d) was associated with pancreatic cancer risk (OR, 1.05; 95% CI, 1.01‐1.10), but tests for interaction between the rs671 A allele and alcohol consumption were nonsignificant, indicating that the effect of alcohol consumption did not vary by genotype. Mediation analysis showed that the nonsignificant total effect (OR, 1.15; 95% CI, 0.92‐1.44) can be decomposed into the carcinogenic direct (OR, 1.34; 95% CI, 1.04‐1.72) and protective indirect effect (OR, 0.86; 95% CI, 0.77‐0.95). This study supports the association between alcohol consumption and pancreatic cancer risk and indicates the potential contribution of the rs671 A allele to pancreatic carcinogenesis through impaired metabolism of known or unknown ALDH2 substrates.
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Affiliation(s)
- Yuriko N Koyanagi
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Isao Oze
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Yumiko Kasugai
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.,Department of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukino Kawakatsu
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Yukari Taniyama
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Kazuo Hara
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Issei Imoto
- Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Hidemi Ito
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.,Department of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.,Department of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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6
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New-Aaron M, Ganesan M, Dagur RS, Kharbanda KK, Poluektova LY, Osna NA. Pancreatogenic Diabetes: Triggering Effects of Alcohol and HIV. BIOLOGY 2021; 10:108. [PMID: 33546230 PMCID: PMC7913335 DOI: 10.3390/biology10020108] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/29/2021] [Accepted: 01/29/2021] [Indexed: 02/07/2023]
Abstract
Multiorgan failure may not be completely resolved among people living with HIV despite HAART use. Although the chances of organ dysfunction may be relatively low, alcohol may potentiate HIV-induced toxic effects in the organs of alcohol-abusing, HIV-infected individuals. The pancreas is one of the most implicated organs, which is manifested as diabetes mellitus or pancreatic cancer. Both alcohol and HIV may trigger pancreatitis, but the combined effects have not been explored. The aim of this review is to explore the literature for understanding the mechanisms of HIV and alcohol-induced pancreatotoxicity. We found that while premature alcohol-inducing zymogen activation is a known trigger of alcoholic pancreatitis, HIV entry through C-C chemokine receptor type 5(CCR5)into pancreatic acinar cells may also contribute to pancreatitis in people living with HIV (PLWH). HIV proteins induce oxidative and ER stresses, causing necrosis. Furthermore, infiltrative immune cells induce necrosis on HIV-containing acinar cells. When necrotic products interact with pancreatic stellate cells, they become activated, leading to the release of both inflammatory and profibrotic cytokines and resulting in pancreatitis. Effective therapeutic strategies should block CCR5 and ameliorate alcohol's effects on acinar cells.
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Affiliation(s)
- Moses New-Aaron
- Department of Environmental Health, Occupational Health and Toxicology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Veteran Affairs Nebraska—Western Iowa Health Care System, Omaha, NE 68105, USA; (M.G.); (R.S.D.); (K.K.K.)
| | - Murali Ganesan
- Veteran Affairs Nebraska—Western Iowa Health Care System, Omaha, NE 68105, USA; (M.G.); (R.S.D.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Raghubendra Singh Dagur
- Veteran Affairs Nebraska—Western Iowa Health Care System, Omaha, NE 68105, USA; (M.G.); (R.S.D.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kusum K. Kharbanda
- Veteran Affairs Nebraska—Western Iowa Health Care System, Omaha, NE 68105, USA; (M.G.); (R.S.D.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Larisa Y. Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Natalia A. Osna
- Department of Environmental Health, Occupational Health and Toxicology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Veteran Affairs Nebraska—Western Iowa Health Care System, Omaha, NE 68105, USA; (M.G.); (R.S.D.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA;
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Takahashi T, Miao Y, Kang F, Dolai S, Gaisano HY. Susceptibility Factors and Cellular Mechanisms Underlying Alcoholic Pancreatitis. Alcohol Clin Exp Res 2020; 44:777-789. [PMID: 32056245 DOI: 10.1111/acer.14304] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 02/03/2020] [Indexed: 12/16/2022]
Abstract
Alcohol is a major cause of acute and chronic pancreatitis. There have been some recent advances in the understanding of the mechanisms underlying alcoholic pancreatitis, which include perturbation in mitochondrial function and autophagy and ectopic exocytosis, with some of these cellular events involving membrane fusion soluble N-ethylmaleimide-sensitive factor receptor protein receptor proteins. Although new insights have been unraveled recently, the precise mechanisms remain complex, and their finer details have yet to be established. The overall pathophysiology of pancreatitis involves not only the pancreatic acinar cells but also the stellate cells and duct cells. Why only some are more susceptible to pancreatitis and with increased severity, while others are not, would suggest that there may be undefined protective factors or mechanisms that enhance recovery and regeneration after injury. Furthermore, there are confounding influences of lifestyle factors such as smoking and diet, and genetic background. Whereas alcohol and smoking cessation and a generally healthy lifestyle are intuitively the advice given to these patients afflicted with alcoholic pancreatitis in order to reduce disease recurrence and progression, there is as yet no specific treatment. A more complete understanding of the pathogenesis of pancreatitis from which novel therapeutic targets could be identified will have a great impact, particularly with the stubbornly high fatality (>30%) of severe pancreatitis. This review focuses on the susceptibility factors and underlying cellular mechanisms of alcohol injury on the exocrine pancreas.
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Affiliation(s)
- Toshimasa Takahashi
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Yifan Miao
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Fei Kang
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Subhankar Dolai
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Herbert Y Gaisano
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
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Teschke R. Alcoholic Liver Disease: Alcohol Metabolism, Cascade of Molecular Mechanisms, Cellular Targets, and Clinical Aspects. Biomedicines 2018; 6:E106. [PMID: 30424581 PMCID: PMC6316574 DOI: 10.3390/biomedicines6040106] [Citation(s) in RCA: 138] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 10/13/2018] [Accepted: 10/20/2018] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease is the result of cascade events, which clinically first lead to alcoholic fatty liver, and then mostly via alcoholic steatohepatitis or alcoholic hepatitis potentially to cirrhosis and hepatocellular carcinoma. Pathogenetic events are linked to the metabolism of ethanol and acetaldehyde as its first oxidation product generated via hepatic alcohol dehydrogenase (ADH) and the microsomal ethanol-oxidizing system (MEOS), which depends on cytochrome P450 2E1 (CYP 2E1), and is inducible by chronic alcohol use. MEOS induction accelerates the metabolism of ethanol to acetaldehyde that facilitates organ injury including the liver, and it produces via CYP 2E1 many reactive oxygen species (ROS) such as ethoxy radical, hydroxyethyl radical, acetyl radical, singlet radical, superoxide radical, hydrogen peroxide, hydroxyl radical, alkoxyl radical, and peroxyl radical. These attack hepatocytes, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells, and their signaling mediators such as interleukins, interferons, and growth factors, help to initiate liver injury including fibrosis and cirrhosis in susceptible individuals with specific risk factors. Through CYP 2E1-dependent ROS, more evidence is emerging that alcohol generates lipid peroxides and modifies the intestinal microbiome, thereby stimulating actions of endotoxins produced by intestinal bacteria; lipid peroxides and endotoxins are potential causes that are involved in alcoholic liver injury. Alcohol modifies SIRT1 (Sirtuin-1; derived from Silent mating type Information Regulation) and SIRT2, and most importantly, the innate and adapted immune systems, which may explain the individual differences of injury susceptibility. Metabolic pathways are also influenced by circadian rhythms, specific conditions known from living organisms including plants. Open for discussion is a 5-hit working hypothesis, attempting to define key elements involved in injury progression. In essence, although abundant biochemical mechanisms are proposed for the initiation and perpetuation of liver injury, patients with an alcohol problem benefit from permanent alcohol abstinence alone.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Leimenstrasse 20, D-63450 Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, Frankfurt/Main, Germany.
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Sun J, Fu J, Zhong Y, Li L, Chen C, Wang X, Wang L, Hou Y, Wang H, Zhao R, Zhang X, Yamamoto M, Xu Y, Pi J. NRF2 mitigates acute alcohol-induced hepatic and pancreatic injury in mice. Food Chem Toxicol 2018; 121:495-503. [PMID: 30248482 DOI: 10.1016/j.fct.2018.09.042] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 09/18/2018] [Accepted: 09/19/2018] [Indexed: 12/20/2022]
Abstract
Binge alcohol drinking is an important health concern and well-known risk factor for the development of numerous disorders. Oxidative stress plays a critical role in the pathogenesis of acute alcoholism. Nuclear factor erythroid 2 like 2 (NRF2) is a master regulator of cellular adaptive response to oxidative insults. However, the role of NRF2 in acute alcoholism and associated pathologies remains unclear. We found that Nrf2-knockout (Nrf2-KO) mice had exaggerated hypoglycemia and hypothermia and increased mortality compared to wildtype mice after binge ethanol exposure. This phenotype was partially rescued by providing warm environment and/or glucose administration. Acute high dose of alcohol exposure resulted in substantially worsened liver and pancreatic injuries in Nrf2-KO mice. Importantly, deficiency of Nrf2 allowed severe pancreatitis and pancreatic β-cell injury with increased insulin secretion and/or leaking during binge ethanol exposure, which contributed to hypoglycemia. In contrast, a clinically used NRF2 activator dimethyl fumarate (DMF) protected against hypoglycemia and lethality induced by acute ethanol exposure. Furthermore, Nrf2-KO mice likely had defective hepatic acetaldehyde metabolism. Taken together, NRF2 plays an important protective role against acute binge alcohol-induced hepatic and pancreatic damage, which may be partially attributable to its primary regulating role in antioxidant response and impact on ethanol metabolism.
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Affiliation(s)
- Jing Sun
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Jingqi Fu
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
| | - Yang Zhong
- Department of Chemistry, School of Fundamental Sciences, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Lu Li
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Chengjie Chen
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Xiaolei Wang
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Linlin Wang
- School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Yongyong Hou
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Huihui Wang
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Rui Zhao
- School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Xixuan Zhang
- Department of Chemistry, School of Fundamental Sciences, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan
| | - Yuanyuan Xu
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Jingbo Pi
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
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10
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Ojeda L, Nogales F, Murillo L, Carreras O. The role of folic acid and selenium against oxidative damage from ethanol in early life programming: a review. Biochem Cell Biol 2018; 96:178-188. [DOI: 10.1139/bcb-2017-0069] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
There are disorders in children, covered by the umbrella term “fetal alcohol spectrum disorder” (FASD), that occur as result of alcohol consumption during pregnancy and lactation. They appear, at least in part, to be related to the oxidative stress generated by ethanol. Ethanol metabolism generates reactive oxygen species and depletes the antioxidant molecule glutathione (GSH), leading to oxidative stress and lipid and protein damage, which are related to growth retardation and neurotoxicity, thereby increasing the incidence of FASD. Furthermore, prenatal and postnatal exposure to ethanol in dams, as well as increasing oxidation in offspring, causes malnutrition of several micronutrients such as the antioxidant folic acid and selenium (Se), affecting their metabolism and bodily distribution. Although abstinence from alcohol is the only way to prevent FASD, it is possible to reduce its harmful effects with a maternal dietary antioxidant therapy. In this review, folic acid and Se have been chosen to be analyzed as antioxidant intervention systems related to FASD because, like ethanol, they act on the methionine metabolic cycle, being related to the endogenous antioxidants GSH and glutathione peroxidase. Moreover, several birth defects are related to poor folate and Se status.
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Affiliation(s)
- Luisa Ojeda
- Department of Physiology, Faculty of Pharmacy, Seville University, Seville, Spain
- Department of Physiology, Faculty of Pharmacy, Seville University, Seville, Spain
| | - Fátima Nogales
- Department of Physiology, Faculty of Pharmacy, Seville University, Seville, Spain
- Department of Physiology, Faculty of Pharmacy, Seville University, Seville, Spain
| | - Luisa Murillo
- Department of Physiology, Faculty of Pharmacy, Seville University, Seville, Spain
- Department of Physiology, Faculty of Pharmacy, Seville University, Seville, Spain
| | - Olimpia Carreras
- Department of Physiology, Faculty of Pharmacy, Seville University, Seville, Spain
- Department of Physiology, Faculty of Pharmacy, Seville University, Seville, Spain
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Wu C, Wu D, Liu Y, Zhong Y. Genetic polymorphism in cytochrome P450 2E1 and alcoholic pancreatitis sus-ceptibility: a meta-analysis. Hippokratia 2018; 22:60-67. [PMID: 31217677 PMCID: PMC6548521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
BACKGROUND The association between cytochrome P450 2E1 (CYP2E1) polymorphism and the risk of alcoholic pancreatitis is contentious. This meta-analysis aimed to demonstrate the association between CYP2E1 RsaI/PstI, or DraI polymorphisms and the susceptibility of alcoholic pancreatitis. MATERIALS AND METHODS We searched for sources and background in Pubmed, Medline, Web of science and CNKI (Chinese national knowledge infrastructure), using the following keywords: "cytochrome P450 2E1" or "CYP2E1", "polymorphism" or "genotype", in combination with "alcoholic pancreatitis". All meta-analyses were performed with Stata 12.0. Subgroup analyses on ethnicity and type of alcoholic pancreatitis were conducted as well. Results: Eleven articles, which met the inclusion criteria, included 595 patients with alcoholic pancreatitis, and 1767 controls. For the general population, our analysis suggested no obvious association between CYP2E1 RsaI/PstI or DraI polymorphisms and the risk of alcoholic pancreatitis. However, in the non-Asian subgroup, significant associations were found between the risk for alcoholic pancreatitis and CYP2E1 RsaI/PstI polymorphism [dominant model: odds ratio (OR) =1.92, 95 % confidence interval (CI): 1.25-2.95, p =0.003; allelic contrast model: OR =1.99, 95 % CI: 1.35-2.92, p <0.001. There was not a significant association found within the Asian group. Meanwhile, the susceptibilities of chronic alcoholic pancreatitis were significantly increased for dominant and allelic contrast models of CYP2E1 RsaI/PstI polymorphism [OR =1.62, 95 % CI: 1.12-2.34; p =0.011; OR =1.62, 95 % CI: 1.17-2.24, p = 0.004, respectively] but not for acute alcoholic pancreatitis for all population. CONCLUSIONS CYP2E1 RsaI/PstI polymorphism may increase the risk of alcoholic pancreatitis in the non-Asian population. Additionally, the CYP2E1 RsaI/PstI polymorphism may increase the susceptibility for chronic alcoholic pancreatitis for all population. HIPPOKRATIA 2018, 22(2): 60-67.
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Affiliation(s)
- C Wu
- ICU Center of the Second Xiangya Hospital, Central South University, Changsha, China
| | - D Wu
- ICU Center of the Second Xiangya Hospital, Central South University, Changsha, China
| | - Y Liu
- Hematological department of the Third Xiangya Hospital, Central South University, Changsha, China
| | - Y Zhong
- ICU Center of the Second Xiangya Hospital, Central South University, Changsha, China
- Hematological department of the Third Xiangya Hospital, Central South University, Changsha, China
- Department of Surgery of University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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12
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Schneider A, Rosendahl J, Bugert P, Weiss C, Unterschütz H, Kylanpää-Bäck ML, Lempinen M, Kemppainen E, Diaconu BL, Ebert MP, Pfützer RH. Genetic Variants in the Manganese Superoxide Dismutase 2 Gene and in the Catalase Gene are not Associated With Alcoholic Chronic Pancreatitis. Alcohol Alcohol 2017; 52:535-541. [PMID: 28655148 DOI: 10.1093/alcalc/agx039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 06/07/2017] [Indexed: 11/14/2022] Open
Abstract
Aims Oxidative stress may contribute to the development of chronic pancreatitis (CP). The enzymes manganese superoxide dismutase 2 (MnSOD, SOD2) and catalase (CAT) counteract free radical activity within the mitochondria and the cytosol. Moreover, CAT activity contributes to the transformation of ethanol to acetaldehyde, a toxic intermediate product of ethanol metabolism, which has been associated with pancreatic damage. Common functional polymorphisms have been described in the MnSOD gene [rs4880, NM_000636.3:c.47 T > C, alanine (ALA) to valine (Val)] and in the CAT promoter region [rs1001179, NG_013339.1:g.4760 C > T]. We investigated whether these polymorphisms are associated with alcoholic CP. Methods We genotyped 470 patients with alcoholic CP for these MnSOD and CAT polymorphisms. We also analysed these variants in 357 healthy control subjects, and in an additional control group of 113 individuals with non-alcoholic CP. We used the age at onset of CP as marker of disease severity and investigated whether different genotypes are associated with different ages at onset. In patients with alcoholic CP, we investigated whether an interaction exists between smoking behaviour and genotypes by comparing genotype distributions in smokers and non-smokers. Results We did not observe significant differences of genotype frequencies between patient groups and controls. In patient groups, we did not find significant differences in the ages at onset between different genotypes. We did not observe an interaction between these polymorphisms. We did not find an association of these variants with smoking behaviour. Conclusions The investigated MnSOD and CAT polymorphisms do not predispose to the development of alcoholic CP. Short summary Patients with alcoholic pancreatitis and controls were genotyped for polymorphisms in oxidative stress genes. There were no significant differences of genotype frequencies between patients and controls, and no association with the age at onset of disease was observed. The polymorphisms are not associated with the development of alcoholic pancreatitis.
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Affiliation(s)
- Alexander Schneider
- Department of Medicine II, University Medical Centre Mannheim, Medical Faculty of the University of Heidelberg, Mannheim, Germany
| | - Jonas Rosendahl
- University Clinic and Policlinic of Internal Medicine I, University Clinic of Halle, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany
| | - Peter Bugert
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim of the University of Heidelberg, German Red Cross Blood Service of Baden-Württemberg-Hessen, Friedrich-Ebert-Straße 107, 68167 Mannheim, Germany
| | - Christel Weiss
- Department of Medical Statistics, University Medical Centre Mannheim, Medical Faculty of the University of Heidelberg, Ludolf-Krehl-Straße 13-17, D-68167 Mannheim, Germany
| | - Heike Unterschütz
- Department of Medicine II, University Medical Centre Mannheim, Medical Faculty of the University of Heidelberg, Mannheim, Germany
| | - Marja-Leena Kylanpää-Bäck
- Department of Surgery, Helsinki University Central Hospital, PO Box 263, Kasarmikatu 11-13, FIN-00029, Helsinki, Finland
| | - Marko Lempinen
- Department of Surgery, Helsinki University Central Hospital, PO Box 263, Kasarmikatu 11-13, FIN-00029, Helsinki, Finland
| | - Esko Kemppainen
- Department of Surgery, Helsinki University Central Hospital, PO Box 263, Kasarmikatu 11-13, FIN-00029, Helsinki, Finland
| | - Brindusa L Diaconu
- 3rd Medical Clinic, University of Medicine and Pharmacy, Str. Victor Babes Nr. 8, 400012 Cluj-Napoca, Romania
| | - Matthias P Ebert
- Department of Medicine II, University Medical Centre Mannheim, Medical Faculty of the University of Heidelberg, Mannheim, Germany
| | - Roland H Pfützer
- Department of Medicine II, University Medical Centre Mannheim, Medical Faculty of the University of Heidelberg, Mannheim, Germany.,Department of Internal Medicine, Klinikum Döbeln, Sörmitzer Str. 10, 04720 Döbeln, Germany
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13
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Bhopale KK, Amer SM, Kaphalia L, Soman KV, Wiktorowicz JE, Shakeel Ansari GA, Kaphalia BS. Proteins Differentially Expressed in the Pancreas of Hepatic Alcohol Dehydrogenase-Deficient Deer Mice Fed Ethanol For 3 Months. Pancreas 2017; 46:806-812. [PMID: 28609370 PMCID: PMC5471625 DOI: 10.1097/mpa.0000000000000835] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVES The aim of this study was to identify differentially expressed proteins in the pancreatic tissue of hepatic alcohol dehydrogenase-deficient deer mice fed ethanol to understand metabolic basis and mechanism of alcoholic chronic pancreatitis. METHODS Mice were fed liquid diet containing 3.5 g% ethanol daily for 3 months, and differentially expressed pancreatic proteins were identified by protein separation using 2-dimensional gel electrophoresis and identification by mass spectrometry. RESULTS Nineteen differentially expressed proteins were identified by applying criteria established for protein identification in proteomics. An increased abundance was found for ribosome-binding protein 1, 60S ribosomal protein L31-like isoform 1, histone 4, calcium, and adenosine triphosphate (ATP) binding proteins and the proteins involved in antiapoptotic processes and endoplasmic reticulum function, stress, and/or homeostasis. Low abundance was found for endoA cytokeratin, 40S ribosomal protein SA, amylase 2b isoform precursor, serum albumin, and ATP synthase subunit β and the proteins involved in cell motility, structure, and conformation. CONCLUSIONS Chronic ethanol feeding in alcohol dehydrogenase-deficient deer mice differentially expresses pancreatic functional and structural proteins, which can be used to develop biomarker(s) of alcoholic chronic pancreatitis, particularly amylase 2b precursor, and 60 kDa heat shock protein and those involved in ATP synthesis and blood osmotic pressure.
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Affiliation(s)
- Kamlesh K. Bhopale
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555
| | - Samir M. Amer
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555
- Department of Forensic Medicine and Clinical Toxicology, Tanta University, Egypt
| | - Lata Kaphalia
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77555
| | - Kizhake V. Soman
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555
- Department of UTMB NHLBI Proteomics Center, The University of Texas Medical Branch, Galveston, TX 77555
| | - John E. Wiktorowicz
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555
- Department of UTMB NHLBI Proteomics Center, The University of Texas Medical Branch, Galveston, TX 77555
| | | | - Bhupendra S. Kaphalia
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555
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Standop J, Schneider M, Ulrich A, Büchler MW, Pour PM. Differences in Immunohistochemical Expression of Xenobiotic-Metabolizing Enzymes Between Normal Pancreas, Chronic Pancreatitis and Pancreatic Cancer. Toxicol Pathol 2016; 31:506-13. [PMID: 14692619 DOI: 10.1080/01926230390226041] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Metabolic activation of many toxins, carcinogens, drugs, and anti-cancer agents is governed by the cytochrome P450 (CYP) drug-metabolizing enzyme system. To help elucidate the role of this enzyme system in the pathogenesis of chronic inflammatory and malignant pancreatic diseases, we compared the immunohistochemical expression pattern of 8 CYP-enzymes in 24 normal, 20 chronic pancreatitis, and 21 pancreatic cancer specimens using antibodies to CYP 1A1, 1A2, 2B6, 2C8/9/19, 2D6, 2E1, and 3A4, and the NADPH cytochrome P450 oxido-reductase (NA-OR). Compared to the normal pancreas, a higher frequency of immunopositivity for CYP 1A2, 2B6, 2C8/9/19, 2D6, and NA-OR was found in chronic pancreatitis, and of all CYPs but 1A2 in pancreatic cancer. On the other hand, CYP 1A1 and 2E1 antibody staining was less frequently observed in chronic pancreatitis. In all specimens with pancreatic polypeptide (PP)-rich regions (pancreas head), more islet cells than ductal and acinar cells were immunopositive. Moreover, the immunoreactivity of islet cells from PP-rich specimens with anti-CYP antibodies was consistently more frequent and intense than in islet cells from PP-poor areas (body and tail). Immunoreactivity for xenobiotic-metabolizing enzymes was frequently observed in the normal pancreas, chronic pancreatitis, and pancreatic cancer, and displayed differences of its frequency and intensity between the 3 groups. Considering immunohistochemical evidence of enzyme expression and pancreatic blood supply together, islet cells appear to be an important and possible early site of CYP-enzyme induction in pancreatic diseases.
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Affiliation(s)
- Jens Standop
- UNMC Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA
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15
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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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16
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Alcohol oxidizing enzymes and ethanol-induced cytotoxicity in rat pancreatic acinar AR42J cells. In Vitro Cell Dev Biol Anim 2013; 50:373-80. [PMID: 24281792 DOI: 10.1007/s11626-013-9700-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Accepted: 09/26/2013] [Indexed: 01/13/2023]
Abstract
Alcoholic chronic pancreatitis (ACP) is a serious inflammatory disease causing significant morbidity and mortality. Due to lack of a suitable animal model, the underlying mechanism of ACP is poorly understood. Chronic alcohol abuse inhibits alcohol dehydrogenase (ADH) and facilitates nonoxidative metabolism of ethanol to fatty acid ethyl esters (FAEEs) in the pancreas frequently damaged during chronic ethanol abuse. Earlier, we reported a concentration-dependent formation of FAEEs and cytotoxicity in ethanol-treated rat pancreatic tumor (AR42J) cells, which express high FAEE synthase activity as compared to ADH and cytochrome P450 2E1. Therefore, the present study was undertaken to investigate the role of various ethanol oxidizing enzymes in ethanol-induced pancreatic acinar cell injury. Confluent AR42J cells were pre-treated with inhibitors of ADH class I and II [4-methylpyrazole (MP)] or class I, II, and III [1,10-phenanthroline (PT)], cytochrome P450 2E1 (trans-1,2-dichloroethylene) or catalase (sodium azide) followed by incubation with 800 mg% ethanol at 37°C for 6 h. Ethanol metabolism, cell viability, cytotoxicity (apoptosis and necrosis), cell proliferation status, and formation of FAEEs in AR42J cells were measured. The cell viability and cell proliferation rate were significantly reduced in cells pretreated with 1,10-PT + ethanol followed by those with 4-MP + ethanol. In situ formation of FAEEs was twofold greater in cells incubated with 1,10-PT + ethanol and ∼1.5-fold in those treated with 4-MP + ethanol vs. respective controls. However, cells treated with inhibitors of cytochrome P450 2E1 or catalase in combination of ethanol showed no significant changes either for FAEE formation, cell death or proliferation rate. Therefore, an impaired ADH class I-III catalyzed oxidation of ethanol appears to be a key contributing factor in ethanol-induced pancreatic injury via formation of nonoxidative metabolites of ethanol.
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17
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Vucević D, Mladenović D, Ninković M, Stanković M, Jorgacević B, Stanković M, de Luka S, Radosavljević T. Influence of aging on ethanol-induced oxidative stress in digestive tract of rats. Hum Exp Toxicol 2013; 32:698-705. [PMID: 23821589 DOI: 10.1177/0960327112467045] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Aging and ethanol induce oxidative stress due to increased prooxidant production and decreased antioxidative capacity. The aim was to investigate the influence of aging on oxidative stress in liver, stomach and pancreas in acute ethanol intoxication. Adult (3 months) and old (18 months) male Wistar rats were divided into the following groups: control (control group rats aged 3 months (C3) and control group rats aged 18 months (C18)) and ethanol-treated groups (ethanol-treated 3-month-old rats (E3) and ethanol-treated 18-month-old rats (E18)). Ethanol was administered in five doses of 2 g/kg at 12-h intervals by orogastric tube. Tissue samples were collected for the determination of oxidative stress parameters. Malondialdehyde (MDA) concentration was increased in all the experimental groups and investigated organs versus C3 group ( p < 0.01). The highest MDA level was observed in the stomach in E18 group when compared with C18 and E3 groups ( p < 0.01). Activity of total superoxide dismutase (SOD) and its isoenzymes (copper-/zinc-SOD and manganese-SOD) in E18 group was significantly decreased when compared with E3 and C18 groups ( p < 0.01). Nitrates and nitrites (NO x ) concentration was increased in stomach and pancreas for all the groups when compared with C3 group ( p < 0.01). Hepatic, gastric and pancreatic NO x level was significantly increased in E18 group when compared with E3 group ( p < 0.01). Moreover, level of NO x in liver and pancreas in E18 group was significantly increased when compared with C18 group ( p < 0.01). Aging potentiates ethanol-induced oxidative stress in liver, stomach and pancreas due to increased lipid peroxidation and nitrosative stress and decreased antioxidative tissue capacity.
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Affiliation(s)
- D Vucević
- Department of Pathophysiology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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18
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Abstract
We and others have shown that chronic alcohol consumption results in the induction of CYP2E1 in the liver. We have also detected for the first time such an induction in the mucosa of the small intestine and the colon. The overall induction of CYP2E1 shows interindividual variations and occurs already following a daily ingestion of 40 g of ethanol after 1 week. CYP2E1 induction is associated with an increased metabolism of ethanol resulting in the generation of reactive oxygen species (ROS) with direct and indirect carcinogenic action. ROS generated by CYP2E1 may lead to lipid peroxidation and lipid peroxidation products such as 4-hydroxynonenal bind to DNA forming highly carcinogenic exocyclic etheno DNA-adducts. The generation of these adducts has been shown in cell cultures in animal experiments as well as in human liver biopsies. CYP2E1 also metabolizes various procarcinogens present in diets and in tobacco smoke to their carcinogenic metabolites. Among these, nitrosamines seem to be the most important carcinogens. CYP2E1 also degrades retinoic acid and retinol to polar metabolites. Metabolism of retinoic acid not only results in the loss of retinoic acid promoting carcinogenesis through an increase in cell proliferation and dedifferentiation but also in generation of polar metabolites with apoptotic properties. We have shown that chlormethiazole is a specific CYP2E1 inhibitor in humans. Chlormethiazole inhibits CYP2E1 activity and thus blocks the formation of DNA adducts in cell cultures, restores retinoic acids in alcohol fed animals and inhibits chemical induced ethanol mediated hepatocarcinogenesis. Thus, there is increasing evidence that CYP2E1 induced by chronic alcohol consumption plays an important role in alcohol mediated carcinogenesis.
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Abstract
OBJECTIVES Alcohol abuse is one of the most common factors associated with acute and chronic pancreatitis. Although it is evident that alcohol abuse can have an important role in the development of pancreatitis, it does not seem that alcohol abuse alone is responsible for this disease. We investigated the involvement of ethanol in the impairment of pancreatic repair after induction of pancreatitis. METHODS A biologically relevant mouse model of alcoholic pancreatitis, combining long-term ethanol consumption and coxsackievirus infection, was used to investigate the effects of ethanol on pancreatic regeneration. Tissues were harvested and analyzed by reverse transcription-polymerase chain reaction and immunoblot. RESULTS These studies demonstrate that long-term ethanol consumption impairs the structural repair of the exocrine pancreas. This is accompanied by a delay in the restitution of lipase expression. In addition, impaired expression of the critical pancreatic transcription factors, PDX1 and PTF1, and the mediator of Notch signaling, HES1, was observed. CONCLUSIONS Long-term ethanol consumption impairs the structural repair and functional restitution of the pancreas after severe injury. These impairments may, in part, be explained by the impaired expression of factors important in the development and maintenance of the exocrine pancreas. Impaired pancreatic regeneration may have a role in the pathogenesis of alcoholic pancreatitis.
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Affiliation(s)
| | - Marc Scheer
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68105
| | - Mallory Suhr
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68105
| | - Dahn L. Clemens
- Nebraska and Western Iowa Veterans Administration Medical Center, Omaha, Nebraska 68105,Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68105,Corresponding Author: Dahn L. Clemens, PhD., Associate Professor Department of Internal Medicine, University of Nebraska Medical Center, Omaha Nebraska 68198-8098, (402) 995-3738,
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Lu D, Ma Y, Zhang W, Bao D, Dong W, Lian H, Huang L, Zhang L. Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT
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Dilated Cardiomyopathy Transgenic Mice. Hypertension 2012; 60:81-9. [DOI: 10.1161/hypertensionaha.112.191478] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cytochrome P450 2E1 (CYP2E1) is a cytochrome P450 enzyme that catalyzes the metabolism of toxic substrates. CYP2E1 is upregulated in heart disease, including the dilated cardiomyopathy (DCM) mouse model. Here, knockdown of CYP2E1 significantly ameliorated the dilated left ventricle, thin wall, and dysfunctional contraction in the cTnT
R141W
and adriamycin-induced DCM mouse models. Interstitial fibrosis, poorly organized myofibrils, and swollen mitochondria with loss of cristae were improved in the myocardium of α-myosin heavy chain (MHC)-cTnT
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×CYP2E1-silence double-transgenic mice when compared with the cTnT
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transgenic mice. Oxidative stress, the activation of caspase 3 and caspase 9, the release of cytochrome
c
, and the apoptosis in the myocardium were significantly decreased in double-transgenic mice compared with the cTnT
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transgenic mice. In summary, the expression of CYP2E1 is upregulated in heart disease and might be induced by hypoxemia in cardiomyopathy. The overexpression of CYP2E1 can enhance the metabolism of endogenous ketones to meet the energy demand of the heart in certain disease states, but the overexpression of CYP2E1 can also increase oxidative stress and apoptosis in the DCM heart. Knockdown or downregulation of CYP2E1 might be a therapeutic strategy to control the development of DCM after mutations of cTnT
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or other factors, because DCM is the third most common cause of heart failure and the most frequent cause of heart transplantation.
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Affiliation(s)
- Dan Lu
- From the Key Laboratory of Human Disease Comparative Medicine, Ministry of Health (D.L., Y.M., W.Z., D.B., W.D., H.L., L.Z.), and Key Laboratory of Human Disease Animal Model, State Administration of Traditional Chinese Medicine (L.H., L.Z.), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, China
| | - Yuanwu Ma
- From the Key Laboratory of Human Disease Comparative Medicine, Ministry of Health (D.L., Y.M., W.Z., D.B., W.D., H.L., L.Z.), and Key Laboratory of Human Disease Animal Model, State Administration of Traditional Chinese Medicine (L.H., L.Z.), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, China
| | - Wei Zhang
- From the Key Laboratory of Human Disease Comparative Medicine, Ministry of Health (D.L., Y.M., W.Z., D.B., W.D., H.L., L.Z.), and Key Laboratory of Human Disease Animal Model, State Administration of Traditional Chinese Medicine (L.H., L.Z.), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, China
| | - Dan Bao
- From the Key Laboratory of Human Disease Comparative Medicine, Ministry of Health (D.L., Y.M., W.Z., D.B., W.D., H.L., L.Z.), and Key Laboratory of Human Disease Animal Model, State Administration of Traditional Chinese Medicine (L.H., L.Z.), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, China
| | - Wei Dong
- From the Key Laboratory of Human Disease Comparative Medicine, Ministry of Health (D.L., Y.M., W.Z., D.B., W.D., H.L., L.Z.), and Key Laboratory of Human Disease Animal Model, State Administration of Traditional Chinese Medicine (L.H., L.Z.), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, China
| | - Hong Lian
- From the Key Laboratory of Human Disease Comparative Medicine, Ministry of Health (D.L., Y.M., W.Z., D.B., W.D., H.L., L.Z.), and Key Laboratory of Human Disease Animal Model, State Administration of Traditional Chinese Medicine (L.H., L.Z.), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, China
| | - Lan Huang
- From the Key Laboratory of Human Disease Comparative Medicine, Ministry of Health (D.L., Y.M., W.Z., D.B., W.D., H.L., L.Z.), and Key Laboratory of Human Disease Animal Model, State Administration of Traditional Chinese Medicine (L.H., L.Z.), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, China
| | - Lianfeng Zhang
- From the Key Laboratory of Human Disease Comparative Medicine, Ministry of Health (D.L., Y.M., W.Z., D.B., W.D., H.L., L.Z.), and Key Laboratory of Human Disease Animal Model, State Administration of Traditional Chinese Medicine (L.H., L.Z.), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, China
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Catanzaro I, Naselli F, Saverini M, Giacalone A, Montalto G, Caradonna F. Cytochrome P450 2E1 variable number tandem repeat polymorphisms and health risks: a genotype-phenotype study in cancers associated with drinking and/or smoking. Mol Med Rep 2012; 6:416-20. [PMID: 22614694 DOI: 10.3892/mmr.2012.914] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 04/25/2012] [Indexed: 11/06/2022] Open
Abstract
Cytochrome P450 2E1 (CYP2E1) is one of the main enzymes involved in the oxidation of ethanol and in the transformation of a number of potentially dangerous compounds. It has various polymorphic sites, one of which is a variable number tandem repeat (VNTR) polymorphism previously described in the 5'-flanking region. The aim of this study was to investigate the genotype-phenotype association between CYP2E1 VNTR polymorphisms and risky health habits in healthy subjects and to analyze the associations between these polymorphisms with drinking- and/or smoking-related cancers. We analyzed 166 healthy subjects by genotyping for the CYP2E1 VNTR polymorphism associated with drinking and/or smoking habits by the more sensitive restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) method, using the NlaIV restriction enzyme. Sixty cases of pancreatic adenocarcinoma (PA) and 66 with hepatocellular carcinoma (HCC), were also genotyped. Statistical analysis was carried out to investigate the genotype-phenotype associations and to compare certain genotypes and cancer. We found 7 genotypes both in the healthy subjects and patients. The A1/A1 genotype was observed to be mainly associated with non-drinkers and -smokers (87.5 and 75.0%, respectively); moreover it was never found in the PA or HCC patients. Conversely, a weak association between A2/A3 with smokers (45.8%) and A4/A4 with drinkers (53.9%) was detected. In addition, the A4/A4 genotype was found to be significantly associated to PA [odds ratio (OR)=3.25; 95% confidence interval (CI) 1.21-7.50]. Our data demonstrate that certain CYP2E1 VNTR genotypes are associated with drinking and/or smoking habits; consequently, they may contribute either to the decreased or increased risk of developing drinking- and/or smoking-related cancers. In particular, we hypothesize that the A1/A1 VNTR genotype may have a protective role against drinking- and/or smoking-related cancers, and that A4/A4 may be a high-risk genotype during the early stages of cancer.
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Affiliation(s)
- Irene Catanzaro
- Department of Molecular and Biomolecular Sciences and Technologies (STEMBIO), Section of Cellular Biology, University of Palermo, I-90128 Palermo, Italy
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Tandon RK, Garg PK. Oxidative stress in chronic pancreatitis: pathophysiological relevance and management. Antioxid Redox Signal 2011; 15:2757-66. [PMID: 21902596 DOI: 10.1089/ars.2011.4115] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
SIGNIFICANCE Chronic pancreatitis (CP) is a progressive, inflammatory disease of the pancreas leading to slow destruction of pancreatic parenchyma and progressive fibrosis. The pathophysiological mechanism of CP is not well understood. RECENT ADVANCES A pathophysiologic role of oxidative stress in CP has, however, been suggested in recent years. Pancreatic acinar cells contain phase I cytochrome P450 (CYP 450) biotransforming enzymes and phase II conjugation reactions for the metabolism of xenobiotics. The oxidative stress in the acinar cell may result from generation of free radicals through CYP induction, concurrent exposure to a chemical that undergoes bioactivation, and insufficiency of micronutrients that are required to sustain antioxidant (AO) capacity. CRITICAL ISSUES Studies have shown that there is indeed a state of oxidative stress as evidenced by increased levels of products of oxidative stress and reduced AO capacity in patients with CP. A recent randomized, controlled trial has shown beneficial effect of AO therapy in CP; a combination of AOs (0.54 g ascorbic acid, 9000 IU β-carotene, 270 IU α-tocopherol, 600 μg organic selenium, and 2 g methionine per day in divided doses) led to significant reductions in pain and oxidative stress in patients with CP. FUTURE DIRECTIONS Similar studies from other centers and multicenter studies should confirm that oxidative stress plays an important role in the pathophysiology of CP and supplementation with AOs leads to significant pain relief in patients with this disease.
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Affiliation(s)
- Rakesh Kumar Tandon
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India.
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Jelski W, Kutylowska E, Laniewska-Dunaj M, Orywal K, Laszewicz W, Szmitkowski M. Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with acute and chronic pancreatitis. Exp Mol Pathol 2011; 91:631-5. [DOI: 10.1016/j.yexmp.2011.06.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Revised: 06/12/2011] [Accepted: 06/13/2011] [Indexed: 12/20/2022]
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Abstract
The association between alcohol consumption and pancreatitis has been recognized for over 100 years. Despite the fact that this association is well recognized, the mechanisms by which alcohol abuse leads to pancreatic tissue damage are not entirely clear. Alcohol abuse is the major factor associated with pancreatitis in the Western world. Interestingly, although most cases of chronic pancreatitis and many cases of acute pancreatitis are associated with alcohol abuse, only a small percentage of individuals who abuse alcohol develop this disease. This situation is reminiscent of the association between alcohol abuse and the incidence of alcoholic liver disease. The liver and the pancreas are developmentally very closely related. Even though these two organs are quite different, they exhibit a number of general structural and functional similarities. Furthermore, the diseases mediated by alcohol abuse in these organs exhibit some striking similarities. The diseases in both organs are characterized by parenchymal cell damage, activation of stellate cells, aberrant wound healing, and fibrosis. Because of the similarities between the liver and the pancreas, and the alcohol-associated diseases of these organs, we may be able to apply much of the knowledge that we have gained regarding the effects of alcohol on the liver to the pancreas.
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Said MM, Ogawa K, Pitchakarn P, Takahashi S, Asamoto M, Shirai T. Cyclooxygenase 2 and Prostaglandin E2 are not Involved in N-Nitrosodiethylamine-Initiated Early Rat Hepatocarcinogenesis. J Toxicol Pathol 2009; 22:263-71. [PMID: 22272001 PMCID: PMC3234601 DOI: 10.1293/tox.22.263] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2009] [Accepted: 07/09/2009] [Indexed: 12/19/2022] Open
Abstract
The present study was undertaken to investigate the effect of dietary
supplementation with nimesulide or eugenol on N-nitrosodiethylamine
(DEN)-initiated early hepatocarcinogenesis in F344 male rats. Both compounds did
not alter the expression of cytochrome P450 (CYP) 2E1, the enzyme that plays a
major role in the activation of DEN to genotoxic products; however, nimesulide
induced the expression of CYP1A1. Western blot analysis revealed that COX-1 and
COX-2 protein expressions were not modulated by DEN compared with normal
controls. Furthermore, post-initiation feeding with nimesulide or eugenol did
not modulate COX-2 protein expression in normal or DEN-treated rats, whereas
eugenol significantly increased the liver prostaglandin E2
(PGE2) levels of DEN-injected animals compared with the DEN
controls. Ultimately, nimesulide or eugenol did not modify DEN-induced
hepatocarcinogenesis as evidenced by insignificant changes in the number and
size of preneoplastic placental glutathione S-transferase (GST-P) positive liver
foci compared with the DEN controls. These results suggest that COX-2, as well
as prostaglandin E2, may play no role in the post-initiation
development of DEN-induced rat hepatocarcinogenesis at an early stage.
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Affiliation(s)
- Mahmoud M. Said
- Department of Biochemistry, Faculty of Science, Ain Shams
University, Cairo 11566, Egypt
- Department of Experimental Pathology and Tumor Biology, Nagoya
City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho,
Mizuho-ku, Nagoya 467-8601, Japan
| | - Kumiko Ogawa
- Department of Experimental Pathology and Tumor Biology, Nagoya
City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho,
Mizuho-ku, Nagoya 467-8601, Japan
| | - Pornsiri Pitchakarn
- Department of Experimental Pathology and Tumor Biology, Nagoya
City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho,
Mizuho-ku, Nagoya 467-8601, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya
City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho,
Mizuho-ku, Nagoya 467-8601, Japan
| | - Makoto Asamoto
- Department of Experimental Pathology and Tumor Biology, Nagoya
City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho,
Mizuho-ku, Nagoya 467-8601, Japan
| | - Tomoyuki Shirai
- Department of Experimental Pathology and Tumor Biology, Nagoya
City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho,
Mizuho-ku, Nagoya 467-8601, Japan
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Mihaljevic AL, Esposito I, Friess H, Kleeff J. Molecular biology, models, and histopathology of chronic pancreatitis and pancreatic cancer. Eur Surg 2009. [DOI: 10.1007/s10353-009-0496-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Siech M, Zhou Z, Zhou S, Bair B, Alt A, Hamm S, Gross H, Mayer J, Beger HG, Tian X, Kornmann M, Bachem MG. Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL). Am J Physiol Gastrointest Liver Physiol 2009; 297:G1163-71. [PMID: 19779015 DOI: 10.1152/ajpgi.90468.2008] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Mechanisms leading to acute pancreatitis after a fat-enriched meal combined with excess alcohol are incompletely understood. We have studied the effects of alcohol and fat (VLDL) on pancreatic acinar cell (PAC) function, oxidative stress, and repair mechanisms by pancreatic stellate cells (PSC) leading to fibrogenesis. To do so, PAC (rat) were isolated and cultured up to 24 h. Ethanol and/or VLDL were added to PAC. We measured PAC function (amylase, lipase), injury (lactic dehydrogenase), apoptosis (TUNEL, Apo2.7, annexin V binding), oxidative stress, and lipid peroxidation (conjugated dienes, malondialdehyde, chemoluminescence); we also measured PSC proliferation (bromodeoxyuridine incorporation), matrix synthesis (immunofluorescence of collagens and fibronectin, fibronectin immunoassay), and fatty acids in PAC supernatants (gas chromatography). Within 6 h, cultured PAC degraded and hydrolyzed VLDL completely. VLDL alone (50 microg/ml) and in combination with alcohol (0.2, 0.5, and 1% vol/vol) induced PAC injury (LDL, amylase, and lipase release) within 2 h through generation of oxidative stress. Depending on the dose of VLDL and alcohol, apoptosis and/or necrosis were induced. Antioxidants (Trolox, Probucol) reduced the cytotoxic effect of alcohol and VLDL. Supernatants of alcohol/VLDL-treated PAC stimulated stellate cell proliferation and extracellular matrix synthesis. We concluded that, in the presence of lipoproteins, alcohol induces acinar cell injury. Our results provide a biochemical pathway for the clinical observation that a fat-enriched meal combined with excess alcohol consumption can induce acinar cell injury (acute pancreatitis) followed by repair mechanisms (proliferation and increased matrix synthesis in PSC).
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Affiliation(s)
- Marco Siech
- Dept. of General and Vascular Surgery, Ostalb-Klinikum Aalen, Germany.
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Abstract
Reactive oxygen and reactive nitrogen species (ROS/RNS) have been implicated in the pathogenesis of acute and chronic pancreatitis. Clinical and basic science studies have indicated that ROS/RNS formation processes are intimately linked to the development of the inflammatory disorders. The detrimental effects of highly reactive ROS/RNS are mediated by their direct actions on biomolecules (lipids, proteins, and nucleic acids) and activation of proinflammatory signal cascades, which subsequently lead to activation of immune responses. The present article summarizes the possible sources of ROS/RNS formation and the detailed signaling cascades implicated in the pathogenesis of pancreatic inflammation, as observed in acute and chronic pancreatitis. A therapeutic ROS/RNS-scavenging strategy has been advocated for decades; however, clinical studies examining such approaches have been inconsistent in their results. Emerging evidence indicates that pancreatitis-inducing ROS/RNS generation may be attenuated by targeting ROS/RNS-generating enzymes and upstream mediators.
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Affiliation(s)
- Po Sing Leung
- Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
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29
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Protective effect of salvianolic acid B on chronic pancreatitis induced by trinitrobenzene sulfonic acid solution in rats. Pancreas 2009; 38:71-7. [PMID: 18766118 DOI: 10.1097/mpa.0b013e3181855d0d] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES To investigate the effects of salvianolic acid B (Sal-B) on pancreatic damage in experimental chronic pancreatitis. METHODS Chronic pancreatitis was induced by infusion of trinitrobenzene sulfonic acid into the pancreatic duct in male Sprague-Dawley rats. From the beginning of 5 weeks, the rats in group 2 were treated with Sal-B by gavage for 8 weeks. Salvianolic acid B was given at a daily dose of 10 mg/kg body weight. At the end of 12 weeks, the levels of serum biochemical indexes were measured on an automatic biochemical analyzer; serum hyaluronic acid and laminin levels were determined by radioimmunoassay; pancreatic tissue malondialdehyde (MDA) was analyzed, and the degree of pancreatic damage was determined. RESULTS The level of serum biochemical indexes were similar in all groups (P > 0.05 for all). Salvianolic acid B treatment did not obviously reduce hyaluronic acid and laminin concentration in blood (P > 0.05). Salvianolic acid B treatment decreased MDA concentration in pancreatic tissue (P < 0.01). Salvianolic acid B clearly improved pancreatic histological findings and prevented the activation of pancreatic stellate cells. CONCLUSIONS Sal-B treatment decreased MDA concentration in pancreatic tissue, attenuated morphological pancreatic damage, and prevented the activation of pancreatic stellate cells in experimental chronic pancreatitis.
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Li J, Guo M, Hu B, Liu R, Wang R, Tang C. Does chronic ethanol intake cause chronic pancreatitis?: evidence and mechanism. Pancreas 2008; 37:189-195. [PMID: 18665082 DOI: 10.1097/mpa.0b013e31816459b7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES To demonstrate the relationship between prolonged alcohol intake and chronic pancreatitis. METHODS Wistar rats were fed diet containing 25% concentration (vol/vol) of ethanol for 6 months. Cholecystokinin (CCK) was quantified by radioimmunoassay. Immunohistochemistry was used to detect alpha-smooth muscle actin, cyclooxygenase 2, and toll-like receptor 4 in rat pancreas. Western-blot was used to quantitatively determine the expression of nuclear factor kappaB and the above inflammatory markers. Pancreatic collagen content was quantified by measuring OH-proline. Superoxide dismutase was measured by colorimetric method. RESULTS In contrast to the control group, there was little histological change in pancreatic tissue but obvious ultrastructural changes in acinar cells of the ethanol group. Cholecystokinin, amylase, and lipase were found reduced in the ethanol group. Chronic ethanol intake did not elicit any change in the expression of alpha-smooth muscle actin, cyclooxygenase 2, toll-like receptor 4, nuclear factor kappaB, pancreatic collagen, and superoxide dismutase. CONCLUSIONS Long-term alcohol consumption did not cause chronic pancreatitis but impaired exocrine pancreatic function. The mechanism behind it could be associated with decreased output of intestinal CCK and lower concentration of pancreatic CCK. Furthermore, the nonoxidative pathway of ethanol metabolism was probably involved in it.
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Affiliation(s)
- Jing Li
- Department of Gastroenterology, State Key Laboratory of Biotherapy of Human Diseases, West China Hospital, Sichuan University, Chengdu, PR China
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Lu XL, Song YH, Fu YB, Si JM, Qian KD. Ascorbic acid alleviates pancreatic damage induced by dibutyltin dichloride (DBTC) in rats. Yonsei Med J 2007; 48:1028-34. [PMID: 18159597 PMCID: PMC2628193 DOI: 10.3349/ymj.2007.48.6.1028] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
PURPOSE Because previous studies have reported depleted antioxidant capacity in patients with chronic pancreatitis (CP), prevention of free radical production has gained importance in antifibrotic treatment strategies for CP. The aim of this study was to investigate the effects of ascorbic acid on oxidative capacity and pancreatic damage in experimental CP. MATERIALS AND METHODS CP was induced in male Sprague-Dawley rats by infusion of dibutyltin dichloride (DBTC) into the tail vein. Ascorbic acid was given intraperitoneally at a daily dose of 10 mg/kg body weight. The treatment groups were as follows: group 1, DBTC plus intraperitoneal physiologic saline; group 2, DBTC plus intraperitoneal ascorbic acid; group 3, solvent plus intraperitoneal physiologic saline; group 4, no operation plus intraperitoneal physiologic saline. Each group contained 15 animals. Treatment was started after CP was established. After 4 weeks of treatment, serum hyaluronic acid and laminin levels were determined by radioimmunoassay, pancreatic tissue oxidative stress was analyzed, and the degree of pancreatic damage was determined. RESULTS Ascorbic acid treatment markedly increased superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) concentrations in pancreatic tissue (p < 0.01 for both). Significant serum hyaluronic acid and laminin reductions were observed in group 2 as compared with group 1 (p < 0.05). However, the serum hyaluronic acid and laminin levels remained elevated when compared with those of groups 3 and 4 (p < 0.05). Histopathologic scores were also lower in animals with CP that underwent ascorbic acid-treatment (p < 0.05). CONCLUSION Ascorbic acid treatment alleviated the degree of oxidative stress and pancreatic damage in rat CP. Antioxidant treatment might be considered a potential option to improve the pathologic process in CP.
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Affiliation(s)
- Xin-Liang Lu
- Department of Gastroenterology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Yan-Hua Song
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310009, China
| | - Yan-Biao Fu
- Department of Pathology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Jian-Min Si
- Institute of Clinical Medicine Research of Sir Run Run Shaw, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Ke-Da Qian
- Department of Gastroenterology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
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Chowdhury P, Gupta P. Pathophysiology of alcoholic pancreatitis: an overview. World J Gastroenterol 2006; 12:7421-7. [PMID: 17167828 PMCID: PMC4087585 DOI: 10.3748/wjg.v12.i46.7421] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2006] [Revised: 08/16/2006] [Accepted: 08/22/2006] [Indexed: 02/06/2023] Open
Abstract
Use of alcohol is a worldwide habit regardless of socio-economic background. Heavy alcohol consumption is a potential risk factor for induction of pancreatitis. The current review cites the updated literature on the alcohol metabolism, its effects on gastrointestinal and pancreatic function and in causing pancreatic injury, genetic predisposition of alcohol induced pancreatitis. Reports describing prospective mechanisms of action of alcohol activating the signal transduction pathways, induction of oxidative stress parameters through the development of animal models are being presented.
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Affiliation(s)
- Parimal Chowdhury
- Department of Physiology and Biophysics, College of Medicine, University of Arkansas for Medical Sciences, 4301 W Markham Street, Little Rock, Arkansas 72205, United States.
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Das D, Mukherjee S, Das AS, Mukherjee M, Mitra C. Aqueous extract of black tea (Camellia sinensis) prevents ethanol+cholecystokinin-induced pancreatitis in a rat model. Life Sci 2006; 78:2194-203. [PMID: 16289561 DOI: 10.1016/j.lfs.2005.09.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2005] [Accepted: 09/07/2005] [Indexed: 12/22/2022]
Abstract
Black Tea Extract (BTE), a phytocompound has been attributed with a plethora of health-promoting actions. We have previously demonstrated that BTE inhibits chronic hepatitis in a rat model induced with high-fat and ethanol (EtOH). This study reports that BTE prevents altered pancreatic acinar cell functions, oxidative stress, inflammatory changes and DNA damage in the EtOH+cholecystokinin (CCK)-induced model of pancreatitis. The EtOH+CCK model rats were administered with BTE, and were examined the activity of pancreatic digestive enzymes (amylase and lipase), proinflammatory cytokines (IL-6 and TNF-alpha), oxidative and antioxidative enzymes (nitric oxide, NO; malondialdehyde, MDA; superoxide dismutase, SOD; catalase, CAT), antioxidant level (glutathione, GSH), histopathological changes and the integrity of genomic DNA. Results show that because of chronic EtOH treatment, serum level of amylase and lipase (two biomarkers for pancreatitis) and pancreatic levels of MDA and NO (two biomarkers of oxidative stress) increased significantly, which could be effectively blunted by BTE. BTE could normalize EtOH+CCK-induced suppressed activities of SOD and CAT, and GSH content of pancreatic tissue. Also, histopathological and inflammatory changes during EtOH+CCK-induced pancreatitis could be blunted by BTE. Furthermore, BTE could effectively reduce EtOH+CCK-induced increase in DNA fragmentation and damage. These findings suggest that BTE prevents pancreatitis caused by chronic EtOH+CCK toxicity presumably by enhancing antioxidant, anti-inflammatory and antiapoptotic activity in rats.
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Affiliation(s)
- Dolan Das
- Department of Physiology, Presidency College, Calcutta, India
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Cartmell MT, Schulz HU, O'Reilly DA, Yang BM, Kielstein V, Dunlop SP, Halangk W, Demaine AG, Kingsnorth AN. Cytochrome P450 2E1 high activity polymorphism in alcohol abuse and end-organ disease. World J Gastroenterol 2005; 11:6445-9. [PMID: 16425414 PMCID: PMC4355784 DOI: 10.3748/wjg.v11.i41.6445] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2005] [Revised: 04/01/2005] [Accepted: 04/02/2005] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate a possible role for a recently identified polymorphism in the gene of cytochrome P450 2E1, the presence of which is associated with high activity of the enzyme. METHODS Two hundred and thirty-nine alcohol consumers, ICD 10.1/.2 (ALC), and 208 normal controls were studied. PCR amplification of the CYP2E1 gene region was performed to assess polymorphic variation. Fisher's exact test was used to assess the data. RESULTS Twelve normal controls (5.8%) possessed the insertion. Five ALC (2.1%) had the insertion; of these 2 of 144 with alcohol induced chronic pancreatitis, none of 28 with alcoholic liver disease and 3 of 67 without end-organ disease had the polymorphism. A significantly Lower frequency of subjects possessed the insertion than normal controls [P=0.049 (genotype analysis P=0.03)]. To further assess, if there was a relationship to alcohol problems per se or end-organ disease, we compared patients with alcohol induced end-organ disease vs alcoholic controls without end-organ disease vs normal controls which again showed a significant difference [P=0.045 (genotype analysis, P=0.011)], further sub-group analysis did not identify which group(s) accounted for these differences. CONCLUSION We have shown the frequencies of this high-activity polymorphism in alcohol related patient groups for the first time. The frequency is significantly less in alcoholics than normal controls, as with high activity polymorphisms of alcohol dehydrogenase. The biological significance, and whether the relevance is solely for alcoholism or is there a relationship to end-organ disease, would benefit from the assessment in the populations with a greater frequency of this polymorphism.
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Affiliation(s)
- Mark T Cartmell
- Department of Surgery, Derriford Hospital, and Department of Molecular Medicine, Plymouth Postgraduate Medical School, PL6 8DH, United Kingdom.
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Vaquero-Raya EC, Molero-Richard X. Especies reactivas de oxígeno en las enfermedades inflamatorias del páncreas: ¿una posible diana terapéutica? GASTROENTEROLOGIA Y HEPATOLOGIA 2005; 28:473-84. [PMID: 16185583 DOI: 10.1157/13078997] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Chronic and acute pancreatitis can be understood as distinct stages of an inflammatory spectrum in the pancreas. Although its pathogenesis is not well defined, oxidative stress seems to be clearly involved in its development. During acute pancreatitis, there is an extraordinary and rapid formation of reactive oxygen species that leads to the extinction of pancreatic antioxidant reserves, causes direct tissue damage and activates oxidative cellular mediators, giving rise to the lesion. However, classical antioxidants have not been shown to have clear benefits in patients with acute pancreatitis. Chronic pancreatitis seems to be the result of a recurrent lesion and defective repair, leading to pancreatic atrophy and fibrosis. In this process, oxidative stress is an efficient stimulus to maintain pancreatic stellar cells active, the fibrogenic motor of chronic pancreatitis. Although antioxidant supplements relieve abdominal pain in these patients, the direction of future antioxidant therapies lies in identifying oxidative mechanisms with the potential for intervention.
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Affiliation(s)
- E C Vaquero-Raya
- Servicio de Aparato Digestivo, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
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Abstract
BACKGROUND Hyperamylasaemia and even acute pancreatitis have been reported in patients with paracetamol poisoning. AIMS To describe the incidence, clinical characteristics, and prognostic implications of hyperamylasaemia in paracetamol poisoning. PATIENTS Six hundred and two patients transferred to a specialized unit with severe paracetamol poisoning and 212 unselected patients admitted from the local region. METHODS Retrospective study based on hospital charts. The optimum threshold of serum amylase to discriminate non-survivors was identified. RESULTS An elevated serum amylase (>100 U/L) occurred in 28 of the unselected patients (13%), in 218 of the transferred patients (36%), and in 118 of 148 patients (80%) with fulminant hepatic failure. Only 33 cases of paracetamol-associated acute pancreatitis were diagnosed. A threshold serum amylase of 150 U/L to discriminate non-survivors had sensitivity 76%, specificity 85%, positive predictive value 33%, and negative predictive value 97%. In a logistic regression analysis, a serum amylase > 150 U/L was associated with an excess mortality (odds ratio 5.0, 2.6-9.7). CONCLUSIONS Hyperamylasaemia is frequent in patients with paracetamol poisoning, whereas clinical acute pancreatitis occurs rarely. The incidence of hyperamylasaemia increases with the degree of hepatic dysfunction. A serum amylase exceeding 1.5 times the upper normal limit indicates a poor prognosis.
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Affiliation(s)
- L E Schmidt
- Department of Hepatology A, Rigshospitalet, Copenhagen, Denmark.
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Clemens DL, Jerrells TR. Ethanol consumption potentiates viral pancreatitis and may inhibit pancreas regeneration: preliminary findings. Alcohol 2004; 33:183-9. [PMID: 15596086 DOI: 10.1016/j.alcohol.2004.07.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2004] [Revised: 06/24/2004] [Accepted: 07/16/2004] [Indexed: 12/25/2022]
Abstract
Alcohol abuse is often associated with acute pancreatitis. The pathogenesis of alcoholic pancreatitis remains poorly understood, in part because of the lack of a suitable animal model to study the mechanism or mechanisms of this disease. It has been proposed that ethanol predisposes or sensitizes the pancreas to the effects of co-factors, and the combination of the effects of ethanol on the pancreas and the actions of these co-factors results in alcoholic pancreatitis. A number of viruses are known to infect the pancreas, and we have suggested that one co-factor that could be involved in the development of alcoholic pancreatitis is a viral infection. One of the most-studied groups of viruses that infect the pancreas and cause pancreatitis in human beings is the coxsackieviruses. We have shown that short-term (5-14 days) and subchronic (>28 days) administration of ethanol to mice increases the severity of coxsackie B3-induced pancreas damage. We hypothesize that consumption of ethanol would result in an impairment of pancreas regeneration after injury, similar to the effect of ethanol on liver regeneration. With the use of the murine model of coxsackie B3-mediated alcoholic pancreatitis we have obtained preliminary data to support the hypothesis. Specifically, consumption of ethanol by mice is associated with changes in the replication of acinar cells and their organization into acini after viral-mediated injury. We believe that this model will be a valuable tool to study the biochemical and molecular mechanisms involved in alcoholic pancreatitis.
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Affiliation(s)
- Dahn L Clemens
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-8090, USA.
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Murdock DJL, Clarke J, Flatt PR, Barnett YA, Barnett CR. Role of CYP2E1 in ketone-stimulated insulin release in pancreatic B-cells. Biochem Pharmacol 2004; 67:875-84. [PMID: 15104240 DOI: 10.1016/j.bcp.2003.10.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The role of CYP2E1 in ketone-stimulated insulin release was investigated using isolated pancreatic islets of Langerhans and two mammalian insulin secreting pancreatic beta-cell lines engineered to stably express human CYP2E1 (designated BRIN BD11h2E1 and INS-1h2E1). Isolated rat pancreatic islets were shown to express the CYP2E1 isoform which was inducible by pretreatment of animals with acetone. The cDNA encoded CYP2E1 was expressed and inducible in the engineered cells as shown by Western blotting. The transfected protein was enzymatically active in the heterologous cells as determined by p-nitrophenol hydroxylation rates (0.176 +/- 0.08 vs. 0.341 +/- 0.08 nmol/min/mg microsomal protein in BRIN BD11 control cells and BRIN BD11h2E1 cells respectively, P < 0.001; 0.204 +/- 0.03 vs. 0.633 +/- 0.102 nmol/min/mg microsomal protein in INS-1 and INS-1h2E1, respectively, P < 0.001). Cultivation of CYP2E1 expressing BRIN BD11h2E1 and INS-1h2E1 cells in 40 mM ethanol increased the rate of p-nitrophenol hydroxylation (0.968 +/- 0.09 nmol/min/mg microsomal protein, P < 0.001 and 0.846 +/- 0.103 nmol/min/mg microsomal protein, P < 0.001, respectively) providing further evidence that the heterologous protein is inducible. Cultivation of control cells with ethanol had no observable effect (0.186 +/- 0.05 and 0.195 +/- 0.03 in BRIN BD11 and INS-1, respectively). These cell lines also express NADPH-cytochrome P450 reductase protein which was enzymatically active (0.632 +/- 0.023 in parental BRIN BD11 vs. 0.657 +/- 0.066 without ethanol and 0.824 +/- 0.014 nmol/min/mg microsomal protein with ethanol in BRIN BD11h2E1, P < 0.05; and 1.568 +/- 0.118 in parental INS-1 vs. 1.607 +/- 0.093 without ethanol and 1.805 +/- 0.066 nmol/min/mg microsomal protein with ethanol in INS-1h2E1, P < 0.05) thereby providing a functional cytochrome P450 system. The insulin secretory response of control cell lines and islets was similar to cell lines and islets which had been chemically pretreated, to induce CYP2E1 expression, in response to known nutrient secretagogues. However, insulin output was significantly higher in pretreated islets (1.3-fold, P < 0.05) and CYP2E1 expressing cell lines (BRIN BD11h2E1 2.3-fold, P < 0.001; INS1-1h2E1 1.6-fold, P < 0.001) when stimulated with the ketone 3-hydroxybutyrate than control islets and parental cell lines respectively. Similar acute exposure to acetoacetate enhanced insulin secretion by 1.3-fold (P < 0.05) in pretreated islets, 2.6-fold (P < 0.001) in ethanol pretreated BRIN BD11h2E1 and 1.4-fold (P < 0.001) in ethanol pretreated INS-1h2E1 cells compared to the respective control islets or ethanol pretreated control parental cells. Therefore, these studies highlight a possible role for CYP2E1 in pancreatic cell dysfunction.
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Affiliation(s)
- Diane J Lees Murdock
- School of Biomedical Sciences, University of Ulster, Coleraine, Co. Londonderry, N. Ireland, BT52 1SA, UK.
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Schaarschmidt T, Merkord J, Adam U, Schroeder E, Kunert-Keil C, Sperker B, Drewelow B, Wacke R. Expression of multidrug resistance proteins in rat and human chronic pancreatitis. Pancreas 2004; 28:45-52. [PMID: 14707729 DOI: 10.1097/00006676-200401000-00007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS The expression of the ABC-transporters MDR-1, MRP1, and MRP-2 was investigated in healthy pancreas and in chronic pancreatitis tissue samples in rats and humans to evaluate their possible involvement in a multidrug resistance of the pancreas with consequences for the pharmacologic treatment of pancreatic diseases. METHODS Human pancreatic tissue samples of healthy tissue and chronic pancreatitis were collected during pancreas surgery. In rats, the time-course of the expression of transporter proteins was studied 14, 28, and 56 days after experimental induction of chronic pancreatitis. The expression of MDR-1, MRP-1, MRP-2, and furthermore, LRP and PAP was investigated by RT-PCR, Real Time TaqManPCR, and immunohistochemistry. RESULTS In rat pancreas, MDR-1 (P-gp) and MRP-1 but in human pancreas MDR-1 (P-gp), MRP-1 and MRP-2 were found to be expressed. Chronic pancreatitis lead to an increased transcription of mRNA of MDR-1 (rat and human) and much lower, MRP-2 (human). CONCLUSIONS The expression of P-gp and related transporters could have impact on the metabolism, distribution, and availability of various compounds, including drugs, in the pancreas. The results indicate that this could be more pronounced in chronic pancreatitis.
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Cano MJ, Murillo ML, Delgado MJ, Carreras O. Effects of ethanol and folic acid consumption during pregnancy and lactation on basal enzymatic secretion in the duodenal juice of offspring rats. Nutrition 2003; 19:778-83. [PMID: 12921889 DOI: 10.1016/s0899-9007(03)00097-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVES Studies on duodenal juice enzyme activities were carried out on suckling Wistar rats born to dams given ethanol during gestation and suckling. The results were compared with offspring of dams given diets containing no ethanol. Comparisons were also made with offspring of dams given ethanol and folic acid supplementation to observe whether a folate supplement could sufficiently reverse the negative effect of ethanol consumption. METHODS The dams were fed increased amounts of ethanol (5% to 20%, vol/vol) in tap water for 4 wk. The maximum quantity, 20% ethanol, was given to the dams during pregnancy and lactation. Offspring animals were randomized into three groups: control (CG), ethanol treated (EG), and ethanol plus folic acid (EFG). RESULTS Body weight at birth and at 21 d after birth and pancreatic weight were lower in offspring after ethanol treatment. Folic acid supplement increased these parameters in the EFG. Under basal conditions, decreases in amylase, lipase, and chymotrypsin activities in the duodenal juice after ethanol treatment were detected. Serum and urine amylase activities also decreased in the EG and EFG. These changes were different in the ethanol-treated progenitors. In these progenitors, ethanol treatment increased serum amylase levels. In the offspring, amylase activities in the EFG decreased with respect to the CG; however, an increase in the EG was observed. In dams the folic acid supplement did not significantly alter the serum amylase activities. Lipase and chymotrypsin activities in the EFG were similar to those in the EG. An increase of serum and urine amylase in the EFG with respect to the EG was found. CONCLUSIONS Our findings indicated that, under basal conditions, ethanol treatment during gestation and lactation negatively affects the digestive function in offspring. The effects of ethanol were slightly attenuated in rats supplemented with folic acid for amylase activities. Although extrapolation from animal studies can be tenuous, the present findings may explain the use of folic acid in the prevention of damage induced by ethanol to increase the amylase levels to physiologic concentrations.
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Affiliation(s)
- Ma José Cano
- Department of Physiology and Zoology, School of Pharmacy, University of Seville, Seville, Spain
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Molero X, Vaquero E, Gómez JA, Alonso A, Guarner L. [New horizons in the mechanisms of acute and chronic pancreatic damage]. GASTROENTEROLOGIA Y HEPATOLOGIA 2003; 26:437-46. [PMID: 12887859 DOI: 10.1016/s0210-5705(03)70387-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- X Molero
- Servei d'Aparell Digestiu. Hospital Universitari Vall d'Hebron. Barcelona. España.
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Chrostek L, Jelski W, Szmitkowski M, Puchalski Z. Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the human pancreas. Dig Dis Sci 2003; 48:1230-3. [PMID: 12870777 DOI: 10.1023/a:1024134520823] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Ethanol metabolism in the pancreas occurs predominantly by way of an nonoxidative pathway to fatty acid ethyl esters but oxidative routes to acetaldehyde also may contribute to injury of pancreatic cells. Three metabolic systems are responsible for the oxidative metabolism of ethanol, among which the cytochrome P-4502E1 and alcohol dehydrogenase have been found in the pancreas. The aims of this study were to detect ADH and ALDH in the human pancreas and to assess which ADH isoenzymes are present in this organ. ADH activity was measured by the photometric method and ADH isoenzyme activity was determined using sensitive and specific substrates. ALDH activity was measured by the fluorometric method. We have shown that the activities of ADH and ALDH are present in the pancreas, although the activity of ALDH was not proportionally as low as ADH activity. The class III isoenzyme exhibited the highest activity of all ADH isoenzymes tested and it was about 7 times higher than the activity of class I. The activities of classes II and IV were low. The activities of ADH isoenzymes of classes I, II, and III in the pancreas of men were significantly higher than in women. This study demonstrates that alcohol dehydrogenase and aldehyde dehydrogenase are present in the pancreas.
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Affiliation(s)
- Lech Chrostek
- Department of Biochemical Diagnostics, Medical Academy, Bialystok, Poland
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Schneider A, Whitcomb DC. Hereditary pancreatitis: a model for inflammatory diseases of the pancreas. Best Pract Res Clin Gastroenterol 2002; 16:347-63. [PMID: 12079262 DOI: 10.1053/bega.2002.0311] [Citation(s) in RCA: 89] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Acute and chronic pancreatitis remain among the most recalcitrant of all diseases to investigation and intervention. In the majority of patients, excessive alcohol consumption is associated with development of the disease. Therefore, several theories have been proposed seeking to explain the relationship between alcohol and the development of acute and chronic pancreatitis. However, recent investigations in hereditary pancreatitis provided important insights into chronic pancreatitis pathogenesis and offer an important model for understanding pancreatic inflammation. This article highlights several advances gained from investigating hereditary pancreatitis kindreds, and reviews the TIGAR-O risk/aetiology classification system. Finally, the major independent theories on development of chronic pancreatitis are reviewed with respect to the SAPE hypothesis of chronic pancreatitis pathogenesis.
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Affiliation(s)
- Alexander Schneider
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, PA 15101, USA
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Tavares DC, Cecchi AO, Jordão AA, Vannucchi H, Takahashi CS. Cytogenetic study of chronic ethanol consumption in rats. TERATOGENESIS, CARCINOGENESIS, AND MUTAGENESIS 2002; 21:361-8. [PMID: 11746250 DOI: 10.1002/tcm.1024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Ethanol was supplied in the drinking water of Wistar rats at a concentration of 20% v/v for up to 30 days. The animals treated with ethanol demonstrated a nonsignificant increase in chromosomal aberration frequency when compared with control animals. The mitotic index values obtained indicated no significant differences between ethanol treatment and control groups. The final weights of control rats were significantly greater than those of the ethanol-treated group. Chronic administration of ethanol showed no clastogenic or cytotoxic effect. After chronic ethanol consumption, the cytochromes P450 activity increases, thus possibly preventing the ethanol that has entered the circulation from reaching excessive levels, leading to metabolic adaptation and/or tolerance.
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Pitchumoni CS. Pathogenesis of alcohol-induced chronic pancreatitis: facts, perceptions, and misperceptions. Surg Clin North Am 2001; 81:379-90. [PMID: 11392424 DOI: 10.1016/s0039-6109(05)70125-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The pathogenesis of chronic pancreatitis secondary to chronic alcoholism is not fully understood. A major hurdle in the understanding of the pathogenesis is the inability to study early lesions of the pancreas and the sequential changes. Facts are few; observations are many. Each new hypothesis argues against all previous hypotheses; however, clinical chronic pancreatitis is initiated by one or more of the mechanisms. Good experimental models for alcoholic pancreatitis are not available, limiting the ability to study the pathogenesis. Additional studies on genetic markers and immunologic mechanisms might explain acinar cell injury, which seems to be the earliest lesion in most, if not all, types of chronic pancreatitis. Opie's common channel and obstruction regurgitation theories seem unrelated to chronic pancreatitis. Although biochemical changes of the pancreatic secretion in alcoholic patients promote protein-plug formation, evidence is too weak to consider protein plug as the earliest change. The theory of necrosis of the acinar cell by some unknown mechanism, subsequently leading to fibrosis, is gaining support; however, it is clear that the pathogenesis of alcoholic pancreatitis is not yet fully understood.
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Szuster-Ciesielska A, Daniluk J, Kandefer-Szerszeń M. Oxidative stress in blood of patients with alcohol-related pancreatitis. Pancreas 2001; 22:261-6. [PMID: 11291927 DOI: 10.1097/00006676-200104000-00006] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
To determine the possible role of oxidative stress in alcoholic pancreatitis, the authors measured the ability of blood neutrophils of 22 patients with acute and 20 patients with chronic alcoholic pancreatitis to produce superoxide anion (O2-) and hydrogen peroxide (H2O2), spontaneously and after in vitro stimulation with phorbol ester and compared it with that of neutrophils isolated from the blood of 16 healthy controls. In addition, they measured serum activities of superoxide dismutase, catalase, and the serum concentration of glutathione peroxidase (GPx). Phorbol ester-induced O2- and H2O2 production in neutrophils of patients with acute and chronic pancreatitis was greater than in controls, but these differences, except of superoxide anion production by neutrophils of patients with chronic pancreatitis, were not statistically significant because of large individual differences. Spontaneous resting production of O2- and H2O2 by neutrophils of patients with chronic pancreatitis was significantly greater than in the controls. Superoxide dismutase and catalase activity was greater in sera of both groups of patients with acute and chronic alcoholic pancreatitis than in controls, but GPx concentration was significantly less in the sera of patients with chronic pancreatitis. Impaired GPx production and increased production of O2- and H2O2 by neutrophils may result in increased lipid peroxidation and could play a role in the pathogenesis of chronic alcoholic pancreatitis.
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Affiliation(s)
- A Szuster-Ciesielska
- Department of Virology oand Immunology, Maria Curie-Skłodowska University, University Medical School, Lublin, Poland
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Yang B, O'Reilly DA, Demaine AG, Kingsnorth AN. Study of polymorphisms in the CYP2E1 gene in patients with alcoholic pancreatitis. Alcohol 2001; 23:91-7. [PMID: 11331106 DOI: 10.1016/s0741-8329(00)00135-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cytochrome P450IIEI (CYP2E1) is an ethanol-inducible enzyme. Recently, several novel polymorphisms in the CYP2E1 gene have been identified. A polymorphism at position -35 [G(-35)T] appears to be of functional significance in transcription assays. The aim of this study was to investigate if this and other polymorphisms, at position -1019 [C(-1019)T], 4808 [G(4808)A], and 7668 [T(7668)A] of the CYP2E1 gene are associated with alcoholic pancreatitis. DNA was extracted from peripheral blood of 38 patients with alcoholic chronic pancreatitis (CP), 19 patients with alcoholic acute pancreatitis (AP), 46 alcoholic controls (AC), and 155 normal controls (NC). The polymorphisms were examined by digestion with the corresponding restriction endonucleases following PCR amplification. The results have shown that the frequencies of the rare alleles of these polymorphisms were not significantly different between the CP, AP, and AC groups and NC. Therefore, our study results suggest to us that the polymorphisms investigated in the CYP2E1 gene are unlikely to be involved in the susceptibility and pathogenesis of alcoholic pancreatitis.
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Affiliation(s)
- B Yang
- Molecular Medicine Research Group, Plymouth Postgraduate Medical School, ITTC Building, University of Plymouth, Tamar Science Park, Derriford Road, PL6 8BX, Plymouth, UK.
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Benický J, Nikodémová M, Scsuková S, Zórad S, Strbák V. Four-week ethanol drinking increases both thyrotropin-releasing hormone (TRH) release and content in rat pancreatic islets. Life Sci 2000; 66:629-39. [PMID: 10794518 DOI: 10.1016/s0024-3205(99)00635-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Ethanol exerts profound effects on the endocrine and exocrine pancreas. Some effects of chronic alcohol consumption on insulin secretion in response to glucose load are similar to those of TRH gene disruption. TRH is present in insulin-producing B-cells of the islets of Langerhans; its role in this location is still not fully explored. To examine the possible effect of long-term in vivo ethanol treatment on pancreatic TRH we compared three groups of rats: a 10% (wt:vol) ethanol-drinking group (E), absolute controls (AC) and pair-fed (PF) group with solid food intake corresponding to that of E. The fluidity of pancreatic membranes was not affected by chronic in vivo exposure of rats to ethanol, but was significantly decreased in PF group. Four-week treatment resulted in significantly higher TRH content in isolated islets of the E group and increased basal and 80 mM isotonic ethanol-induced secretion compared to AC and PF. Plasma levels of insulin, C-peptide, IGF-I, and glycemia were, however, not affected by ethanol treatment. Cell swelling, which can be induced by the presence of permeants (e.g. ethanol) in an isotonic extracellular medium, is a strong stimulus for secretion in various types of cells. In the present study, isosmotic ethanol (40, 80, and 160 mM) induced dose-dependent release of TRH and insulin from adult rat pancreatic islets in vitro. The same concentrations were not effective when applied in a hyperosmotic medium (addition of ethanol directly to the medium), thus indicating the participation of cell swelling in the ethanol-induced secretion. In conclusion, chronic ethanol treatment significantly affected pancreatic TRH and this effect might be mediated by cell swelling. The role of these changes in the profound effect of ethanol on the endocrine and exocrine pancreas remains to be established.
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Affiliation(s)
- J Benický
- Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic
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Lieber CS. Microsomal Ethanol-Oxidizing System (MEOS): The First 30 Years (1968-1998)-A Review. Alcohol Clin Exp Res 1999. [DOI: 10.1111/j.1530-0277.1999.tb04217.x] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Abstract
Ethanol and other short-chain alcohols elicit a number of cellular responses that are potentially cytotoxic and, to some extent, independent of cell type. Aberrations in phospholipid and fatty acid metabolism, changes in the cellular redox state, disruptions of the energy state, and increased production of reactive oxygen metabolites have been implicated in cellular damage resulting from acute or chronic exposure to short-chain alcohols. Resulting disruptions of intracellular signaling cascades through interference with the synthesis of phosphatidic acid, decreases in phosphorylation potential and lipid peroxidation are mechanisms by which solvent alcohols can affect the rate of cell proliferation and, consequently, cell number. Nonoxidative metabolism of short-chain alcohols, including phospholipase D-mediated synthesis of alcohol phospholipids, and the synthesis of fatty acid alcohol esters are additional mechanisms by which alcohols can affect membrane structure and compromise cell function.
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Affiliation(s)
- R C Baker
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505, USA.
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