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Yu M, Chen Q, Lu YP. Aldehyde dehydrogenase 2 family member repression promotes colorectal cancer progression by JNK/p38 MAPK pathways-mediated apoptosis and DNA damage. World J Gastrointest Oncol 2024; 16:3230-3240. [PMID: 39072174 PMCID: PMC11271775 DOI: 10.4251/wjgo.v16.i7.3230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 04/29/2024] [Accepted: 05/17/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Aldehyde (ALDH2) dysfunction has been verified to contribute to human cancers. AIM To investigate the molecular mechanism and biological function of ALDH2 in colorectal cancer (CRC) progression. METHODS Human CRC cells with high expression of ALDH2 were screened. After shRNA ALDH2 (sh-ALDH2) transfection, phenotypes [proliferation, apoptosis, acetaldehyde (ACE) accumulation, DNA damage] of CRC cells were verified using cell counting kit-8, flow cytometry, ACE assay, and comet assays. Western blotting was used for evaluation of the apoptosis proteins (Bax and Bcl-2) and JNK/p38 MAPK pathway-associated proteins. We subjected CVT-10216 (a selective ALDH2 inhibitor) to nude mice for establishment of SK-CO-1 mouse xenograft model and observed the occurrence of CRC. RESULTS The inhibition of ALDH2 could promote the malignant structures of CRC cells, including apoptosis, ACE level, and DNA damage, and cell proliferation was decreased in the sh-ALDH2 group, whereas ALDH2 agonist Alda-1 reversed features. ALDH2 repression can cause ACE accumulation, whereas ACE enhanced CRC cell features related to increased DNA damage. Additionally, ALDH2 repression led to JNK/P38 MAPK activation, and apoptosis, ACE accumulation, and DNA damage were inhibited after p38 MAPK inhibitor SB203580 and JNK inhibitor SP600125 addition. ACE accumulation and raised DNA damage were recognized in CVT-10216 treated-mouse tumor tissues in vivo. CONCLUSION The repression of ALDH2 led to ACE accumulation, inducing cell apoptosis and DNA damage by the JNK/p38 MAPK signaling pathway activation in CRC.
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Affiliation(s)
- Miao Yu
- Department of Surgical Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Qian Chen
- Clinical School of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Yi-Ping Lu
- Department of Surgical Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
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2
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Ueno F, Matsushita S, Hara S, Oshima S, Roh S, Ramchandani VA, Mimura M, Uchida H. Influence of alcohol and acetaldehyde on cognitive function: findings from an alcohol clamp study in healthy young adults. Addiction 2022; 117:934-945. [PMID: 34735038 DOI: 10.1111/add.15733] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 10/18/2021] [Indexed: 11/28/2022]
Abstract
AIMS To investigate the acute effects of intravenous alcohol and its metabolite acetaldehyde on cognitive function in healthy individuals. DESIGN Experimental pre-test/post-test design. SETTING Kurihama Medical and Addiction Center, Japan. PARTICIPANTS A total of 298 healthy Japanese people age 20 to 24 years. MEASUREMENTS Participants underwent an intravenous alcohol infusion with a target blood alcohol concentration (BAC) of 0.50 mg/mL for 180 minutes. Participants completed the continuous performance test (CPT) for sustained attention, the paced auditory serial addition test (PASAT) for working memory, and the reaction time test (RTT) for speed/accuracy, along with the blood test for BAC and blood acetaldehyde concentration (BAAC) at baseline, 60 and 180 minutes. FINDINGS Although the target BAC was maintained during the infusion, BAAC peaked at 30 minutes and then gradually declined (η2 = 0.18, P < 0.01). The CPT scores worsened, and the changes between 0 and 60 minutes were correlated with BAAC (correct detection, η2 = 0.09, P < 0.01; r = -0.34, P < 0.01; omission errors, η2 = 0.08, P < 0.01; r = 0.34, P < 0.01). PASAT scores improved through 180 minutes, whereas the changes between 0 and 60 minutes were negatively correlated with BAAC (task one, η2 = 0.02, P < 0.01; r = -0.25, P < 0.01; task two, η2 = 0.03, P < 0.01; r = -0.28, P < 0.01). Although RTTs worsened, they were not associated with BAC or BAAC. None of these comparisons maintained the time effect after controlling for body height. CONCLUSIONS Acetaldehyde exposure following acute intravenous alcohol appears to have a negative impact on sustained attention and working memory, whereas there seems to be only a minor effect of moderate alcohol concentration on speed and accuracy.
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Affiliation(s)
- Fumihiko Ueno
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan.,Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.,Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Canada
| | - Sachio Matsushita
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Sachiko Hara
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Shunji Oshima
- Core Technology Laboratories, Asahi Quality & Innovations, Ltd., Moriya, Japan
| | - Sungwon Roh
- Department of Psychiatry, Hanyang University College of Medicine, Seoul, South Korea
| | - Vijay A Ramchandani
- Section on Human Psychopharmacology, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Masaru Mimura
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Hiroyuki Uchida
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
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Mabe K, Inoue K, Kamada T, Kato K, Kato M, Haruma K. Endoscopic screening for gastric cancer in Japan: Current status and future perspectives. Dig Endosc 2022; 34:412-419. [PMID: 34143908 DOI: 10.1111/den.14063] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/18/2022]
Abstract
The revised 2014 Japanese Guidelines for Gastric Cancer Screening approved gastric endoscopy for use in population-based screening. Thus, it is expected that gastric cancer will be detected earlier, and gastric cancer mortality further decreased, with the widespread use of endoscopy and Helicobacter pylori eradication therapy. However, due to an increasingly aging population and relatively low gastric cancer screening rates, gastric cancer remains the leading cause of cancer death in Japan. While the era of endoscopic gastric cancer screening has begun, it does present challenges, such as limited/varying regional availability of endoscopists. This review describes the history of gastric cancer screening in Japan, achievements in endoscopic gastric cancer screening in Japan and Korea, efforts underway to improve screening by stratifying individuals according to gastric cancer risk, and initiatives by the Japan Gastroenterological Endoscopy Society aimed at improving screening, including the implementation of a board certification program for screening endoscopists.
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Affiliation(s)
- Katsuhiro Mabe
- Junpukai Health Maintenance Center-Kurashiki, Okayama, Japan
| | | | - Tomoari Kamada
- Department of Health Care Medicine, Kawasaki Medical School, Okayama, Japan
| | - Katsuaki Kato
- Cancer Detection Center, Miyagi Cancer Society, Miyagi, Japan
| | - Mototsugu Kato
- National Hospital Organization Hakodate National Hospital, Hokkaido, Japan
| | - Ken Haruma
- Junpukai Health Maintenance Center, Okayama, Japan
- Division of Gastroenterology, Department of Internal Medicine 2, Kawasaki Medical School, Okayama, Japan
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Rodriguez FD, Coveñas R. Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers. Cancers (Basel) 2021; 13:cancers13143548. [PMID: 34298760 PMCID: PMC8306032 DOI: 10.3390/cancers13143548] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/01/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Of all yearly deaths attributable to alcohol consumption globally, approximately 12% are due to cancers, representing approximately 0.4 million deceased individuals. Ethanol metabolism disturbs cell biochemistry by targeting the structure and function of essential biomolecules (proteins, nucleic acids, and lipids) and by provoking alterations in cell programming that lead to cancer development and cancer malignancy. A better understanding of the metabolic and cell signaling realm affected by ethanol is paramount to designing effective treatments and preventive actions tailored to specific neoplasias. Abstract The World Health Organization identifies alcohol as a cause of several neoplasias of the oropharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. We review ethanol’s nonoxidative and oxidative metabolism and one-carbon metabolism that encompasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals, which interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol’s effects on stem cells, which are responsible for building and repairing tissues, are reviewed. Cancer stem cells (CSCs) of different origins suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with the consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underline and discuss potential targets that show more sensitivity to ethanol’s action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological intervention. Specifically, research should pay attention to re-establishing metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.
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Affiliation(s)
- Francisco D. Rodriguez
- Department of Biochemistry and Molecular Biology, Faculty of Chemistry, University of Salamanca, 37007 Salamanca, Spain
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), 37007 Salamanca, Spain;
- Correspondence: ; Tel.: +34-677-510-030
| | - Rafael Coveñas
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), 37007 Salamanca, Spain;
- Institute of Neurosciences of Castilla y León (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems, University of Salamanca, 37007 Salamanca, Spain
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Zhang H, Xia Y, Wang F, Luo M, Yang K, Liang S, An S, Wu S, Yang C, Chen D, Xu M, Cai M, To KKW, Fu L. Aldehyde Dehydrogenase 2 Mediates Alcohol-Induced Colorectal Cancer Immune Escape through Stabilizing PD-L1 Expression. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2003404. [PMID: 34026438 PMCID: PMC8132160 DOI: 10.1002/advs.202003404] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 02/21/2021] [Indexed: 05/06/2023]
Abstract
Despite the great success of immunotherapy in a small subset of cancer patients, most colorectal cancer (CRC) patients do not respond to programmed cell death receptor 1 (PD-1) blockade immunotherapy. There is an urgent medical need to elucidate how cancer cells evade immune response and to develop novel means to boost the efficacy of immune checkpoint inhibitors. In this study, alcohol induces ligand programmed cell death receptor 1 (PD-L1) expression of CRC cells in vitro and in vivo. Alcohol exposure is shown to induce aldehyde dehydrogenase 2 (ALDH2) expression that is a crucial enzyme involved in alcohol metabolism, and low level of lymphocytes infiltration in the murine CRC model and patients. Intriguingly, ALDH2 and PD-L1 protein expression are positively correlated in tumor tissues from the CRC patients. Mechanistically, ALDH2 stabilizes PD-L1 protein expression by physically interacting with the intracellular segment of PD-L1 and inhibiting its proteasome-dependent degradation mediated by an E3 ubiquitin ligase Speckle Type POZ Protein (SPOP). Importantly, inhibition of ALDH2 reduces PD-L1 protein in CRC cells and promotes tumor-infiltrating T cells (TILs) infiltration, presumably leading to the significant potentiation of anti-PD-1 antibody efficacy in a mouse CT26 CRC model. The findings highlight a crucial role played by ALDH2 to facilitate alcohol-mediated tumor escape from immunity surveillance and promote tumor progression.
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Affiliation(s)
- Hong Zhang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Yuhui Xia
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Fang Wang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Min Luo
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Ke Yang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Shaobo Liang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Sainan An
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Shaocong Wu
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Chuan Yang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Da Chen
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Meng Xu
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Muyan Cai
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Kenneth K. W. To
- School of PharmacyFaculty of MedicineThe Chinese University of Hong KongHong KongChina
| | - Liwu Fu
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
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Different Expression of Aldehyde Dehydrogenases 1A1 and 2 in Oral Leukoplakia With Epithelial Dysplasia and in Oral Squamous Cell Carcinoma. Appl Immunohistochem Mol Morphol 2020; 27:537-542. [PMID: 29189260 DOI: 10.1097/pai.0000000000000612] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Oral potentially malignant disorders (OPMD) may develop malignant characteristics and transform into oral squamous cell carcinoma (OSCC) in a range of 1% to 2% of cases. Chronic alcohol consumption is associated with carcinogenesis, but its mechanism has not yet been fully elucidated. ALDH1A1 and 2, isoenzymes responsible for aldehyde oxidation involved in ethanol metabolism may be associated with the development of malignant head and neck neoplasms. The aim of this study was to analyze the expression of ALDH1A1 and ALDH2 in oral leukoplakia with epithelial dysplasia (OLP) and OSCC. A retrospective study was conducted on 27 cases of OLP and 30 cases of OSCC. Clinical data were obtained from medical records, and all cases were classified as mild, moderate, and severe for OLP, and well-differentiated, moderately differentiated, or poorly differentiated for OSCC cases. The ALDH1A1 and ALDH2 expression in OLP and OSCC was evaluated by the immunohistochemical technique. There was predominance of the male sex, in both OLP and OSCC cases. Oral tongue was the most affected site in both groups. OLP showed positive protein expression of ALDH1A1 in all cases, both basal and suprabasal epithelial layers, whereas ALDH2 showed less protein expression. In OSCC, the immunohistochemical reaction for ALDH1A1 expression was negative in 70%, whereas ALDH2 expression was positive in all cases. This study demonstrated the gradual loss of ALDH1A1 expression in OSCC in comparison with OLP, and the increased ALDH2 expression in OSCC.
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7
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Di Rocco G, Baldari S, Pani G, Toietta G. Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells. Cell Mol Life Sci 2019; 76:231-244. [PMID: 30306211 PMCID: PMC6339663 DOI: 10.1007/s00018-018-2931-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 09/10/2018] [Accepted: 10/01/2018] [Indexed: 12/13/2022]
Abstract
Stem cells drive embryonic and fetal development. In several adult tissues, they retain the ability to self-renew and differentiate into a variety of specialized cells, thus contributing to tissue homeostasis and repair throughout life span. Alcohol consumption is associated with an increased risk for several diseases and conditions. Growing and developing tissues are particularly vulnerable to alcohol's influence, suggesting that stem- and progenitor-cell function could be affected. Accordingly, recent studies have revealed the possible relevance of alcohol exposure in impairing stem-cell properties, consequently affecting organ development and injury response in different tissues. Here, we review the main studies describing the effects of alcohol on different types of progenitor/stem cells including neuronal, hepatic, intestinal and adventitial progenitor cells, bone-marrow-derived stromal cell, dental pulp, embryonic and hematopoietic stem cells, and tumor-initiating cells. A better understanding of the nature of the cellular damage induced by chronic and episodic heavy (binge) drinking is critical for the improvement of current therapeutic strategies designed to treat patients suffering from alcohol-related disorders.
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Affiliation(s)
- Giuliana Di Rocco
- Department of Research, Advanced Diagnostic, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, Italy
| | - Silvia Baldari
- Department of Research, Advanced Diagnostic, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, Italy
| | - Giovambattista Pani
- Institute of General Pathology, Laboratory of Cell Signaling, Catholic University Medical School, Largo F. Vito 1, 00168, Rome, Italy
| | - Gabriele Toietta
- Department of Research, Advanced Diagnostic, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, Italy.
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Matsumoto A. The Bidirectional Effect of Defective ALDH2 Polymorphism and Disease Prevention. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1193:69-87. [PMID: 31368098 DOI: 10.1007/978-981-13-6260-6_4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Despite the role of aldehyde dehydrogenase 2 (ALDH2) in the detoxification of endogenous aldehydes, the defective polymorphism (rs671), which is highly prevalent among East Asians, does not show a serious phenotype, such as congenital abnormality. However, unfavorable and favorable impacts of the variant allele, ALDH2*2, on various disease risks have been reported. The underlying mechanisms are often complicated due to the compensatory aldehyde detoxification systems. As the phenotypes emerge due to overlapping environmental factors (e.g., alcohol intake and tobacco smoke) or individual vulnerabilities (e.g., aging and apolipoprotein E ε4 allele), polymorphism is therefore considered to be important in the field of preventative medicine. For example, it is important to recognize that ALDH2*2 carriers are at a high risk of alcohol drinking-related cancers; however, their drinking habit has less adverse effects on physiological indices, such as blood pressure, body mass index, levels of lipids, and hepatic deviation enzymes in the blood, than in non-ALDH2*2 carriers. Therefore, opportunities to reconsider their excessive drinking habit before adverse events occur can be missed. To perform effective disease prevention, the effects of ALDH2*2 on various diseases and the biological mechanisms should be clarified.
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Affiliation(s)
- Akiko Matsumoto
- Department of Social Medicine, Saga University School of Medicine, Saga, Japan.
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9
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Matsumoto A. [Importance of an Aldehyde Dehydrogenase 2 Polymorphism in Preventive Medicine]. Nihon Eiseigaku Zasshi 2018; 73:9-20. [PMID: 29386454 DOI: 10.1265/jjh.73.9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Unlike genetic alterations in other aldehyde dehydrogenase (ALDH) isozymes, a defective ALDH2 polymorphism (rs671), which is carried by almost half of East Asians, does not show a clear phenotype such as a shortened life span. However, impacts of a defective ALDH2 allele, ALDH2*2, on various disease risks have been reported. As ALDH2 is responsible for the detoxification of endogenous aldehydes, a negative effect of this polymorphism is predicted, but bidirectional effects have been actually observed and the mechanisms underlying such influences are often complex. One reason for this complexity may be the existence of compensatory aldehyde detoxification systems and the secondary effects of these systems. There are many issues to be addressed with regard to the ALDH2 polymorphism in the field of preventive medicine, including the following concerns. First, ALDH2 in the fetal stage plays a role in aldehyde detoxification; therefore, prenatal health effects of environmental aldehyde exposure are of concern for ALDH2*2-carrying fetuses. Second, ALDH2*2 carriers are at high risk of drinking-related cancers. However, their drinking habits result in less worsening of physiological findings, such as energy metabolism index and liver functions, compared with non-ALDH2*2 carriers, and therefore opportunities to detect excessive drinking can be lost. Third, personalized medicine such as personalized prescriptions for ALDH2*2 carriers will be required in the clinical setting, and accumulation of evidence is awaited. Lastly, since the ALDH2 polymorphism is not considered in workers' limits of exposure to aldehydes and their precursors, efforts to lower exposure levels beyond legal standards are required.
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Affiliation(s)
- Akiko Matsumoto
- Department of Social Medicine, Saga University School of Medicine
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Matejcic M, Gunter MJ, Ferrari P. Alcohol metabolism and oesophageal cancer: a systematic review of the evidence. Carcinogenesis 2017. [PMID: 28645180 DOI: 10.1093/carcin/bgx067] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Alcohol is a major risk factor for oesophageal squamous cell carcinoma (OSCC), the most prevalent histological subtype of oesophageal cancer (OC) worldwide. The metabolism of alcohol is regulated by specific enzymes whose activity and expression is influenced by genetic polymorphisms. We conducted a systematic review of current epidemiological evidence of the relationship between alcohol intake and OC risk, including the role of tobacco smoking and functional polymorphisms of alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). Potential biological mechanisms underlying oesophageal carcinogenesis are also discussed. Frequency and intensity of alcohol intake have been consistently associated with an increased risk of OSCC in regions with low and high incidence of the disease. The highest risk was reported among tobacco smokers, whereas the association between alcohol and OSCC risk was weak in the absence of tobacco use. The ADH1B, ADH1C and ALDH2 gene polymorphisms influence the risk of OSCC through modulation of acetaldehyde metabolism and propensity to alcohol intake. These functional variants may be suitable proxies of alcohol exposure for use in Mendelian randomization studies if complemented by reported alcohol intake data. Recent epidemiological and experimental studies investigating the role of alcohol consumption in OC development have implicated the microbiome as a new promising avenue for research, which entail novel potential mechanisms of alcohol-related oesophageal carcinogenesis. Microbial communities associated with alcohol consumption might be used as biomarkers to raise the potential of intervening among susceptible individuals.
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Affiliation(s)
- Marco Matejcic
- Nutritional Epidemiology Group, International Agency for Research on Cancer, World Health Organization, 150 cours Albert Thomas, 69372 Lyon CEDEX 08, France
| | - Marc J Gunter
- Nutritional Epidemiology Group, International Agency for Research on Cancer, World Health Organization, 150 cours Albert Thomas, 69372 Lyon CEDEX 08, France
| | - Pietro Ferrari
- Nutritional Epidemiology Group, International Agency for Research on Cancer, World Health Organization, 150 cours Albert Thomas, 69372 Lyon CEDEX 08, France
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11
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Matsumoto A. [Fundamental Properties of Aldehyde Dehydrogenase 2 (ALDH2) and the Importance of the ALDH2 Polymorphism]. Nihon Eiseigaku Zasshi 2016; 71:55-68. [PMID: 26832618 DOI: 10.1265/jjh.71.55] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Human aldehyde dehydrogenase 2 (ALDH2) is a 56 kDa mitochondrial protein that forms homodimers through hydrogen bonding interactions between the Glu487 and Arg475 residues of two ALDH2 proteins. Two ALDH2 homodimers can interact to form an ALDH2 tetramer. ALDH2 is widely distributed throughout the organs of the body. In addition to its dehydrogenase activity, ALDH2 also exhibits esterase and reductase activities, with the main substrates for these three activities being aldehydes, 4-nitrophenyl acetate and nitroglycerin, respectively. ALDH2 can be readily inhibited by a wide variety of endogenous and exogenous chemicals, but the induction or activation of this enzyme remains unlikely. The polymorphism of ALDH2 to the corresponding ALDH2*2 variant results in a severe deficiency in ALDH2 activity, and this particular polymorphism is prevalent among people of Mongoloid descent. It seems reasonable to expect that people with the ALDH2*2 variant would be more vulnerable to stress and diseases because ALDH2 defends the human body against toxic aldehydes. However, it has been suggested that people with the ALDH2*2 variant are protected by alternative stress-defending systems. The ALDH2*2 variant has been reported to be associated with many different kinds of diseases, although the mechanisms underlying these associations have not yet been elucidated. ALDH2 polymorphism has a significant impact on human health; further studies are therefore required to determine the practical implications of this polymorphism in the fields of preventive and clinical medicine.
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Affiliation(s)
- Akiko Matsumoto
- Department of Social Medicine, Saga University School of Medicine
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12
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Protective role of ALDH2 against acetaldehyde-derived DNA damage in oesophageal squamous epithelium. Sci Rep 2015; 5:14142. [PMID: 26374466 PMCID: PMC4570974 DOI: 10.1038/srep14142] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022] Open
Abstract
Acetaldehyde is an ethanol-derived definite carcinogen that causes oesophageal squamous cell carcinoma (ESCC). Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme that eliminates acetaldehyde, and impairment of ALDH2 increases the risk of ESCC. ALDH2 is produced in various tissues including the liver, heart, and kidney, but the generation and functional roles of ALDH2 in the oesophagus remain elusive. Here, we report that ethanol drinking increased ALDH2 production in the oesophagus of wild-type mice. Notably, levels of acetaldehyde-derived DNA damage represented by N2-ethylidene-2′-deoxyguanosine were higher in the oesophagus of Aldh2-knockout mice than in wild-type mice upon ethanol consumption. In vitro experiments revealed that acetaldehyde induced ALDH2 production in both mouse and human oesophageal keratinocytes. Furthermore, the N2-ethylidene-2′-deoxyguanosine levels increased in both Aldh2-knockout mouse keratinocytes and ALDH2-knockdown human keratinocytes treated with acetaldehyde. Conversely, forced production of ALDH2 sharply diminished the N2-ethylidene-2′-deoxyguanosine levels. Our findings provide new insight into the preventive role of oesophageal ALDH2 against acetaldehyde-derived DNA damage.
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Implications of acetaldehyde-derived DNA adducts for understanding alcohol-related carcinogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 815:71-88. [PMID: 25427902 DOI: 10.1007/978-3-319-09614-8_5] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Among various potential mechanisms that could explain alcohol carcinogenicity, the metabolism of ethanol to acetaldehyde represents an obvious possible mechanism, at least in some tissues. The fundamental principle of genotoxic carcinogenesis is the formation of mutagenic DNA adducts in proliferating cells. If not repaired, these adducts can result in mutations during DNA replication, which are passed on to cells during mitosis. Consistent with a genotoxic mechanism, acetaldehyde does react with DNA to form a variety of different types of DNA adducts. In this chapter we will focus more specifically on N2-ethylidene-deoxyguanosine (N2-ethylidene-dG), the major DNA adduct formed from the reaction of acetaldehyde with DNA and specifically highlight recent data on the measurement of this DNA adduct in the human body after alcohol exposure. Because results are of particular biological relevance for alcohol-related cancer of the upper aerodigestive tract (UADT), we will also discuss the histology and cytology of the UADT, with the goal of placing the adduct data in the relevant cellular context for mechanistic interpretation. Furthermore, we will discuss the sources and concentrations of acetaldehyde and ethanol in different cell types during alcohol consumption in humans. Finally, in the last part of the chapter, we will critically evaluate the concept of carcinogenic levels of acetaldehyde, which has been raised in the literature, and discuss how data from acetaldehyde genotoxicity are and can be utilized in physiologically based models to evaluate exposure risk.
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Dura P, Berkers T, van Veen EM, Salomon J, te Morsche RHM, Roelofs HMJ, Kristinsson JO, Wobbes T, Witteman BJM, Tan ACITL, Drenth JPH, Peters WHM. Polymorphisms in alcohol-metabolizing enzymes and esophageal carcinoma susceptibility: a Dutch Caucasian case–control study. J Hum Genet 2013; 58:742-8. [DOI: 10.1038/jhg.2013.95] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 07/30/2013] [Accepted: 08/13/2013] [Indexed: 02/07/2023]
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Alcohol and aldehyde dehydrogenase polymorphisms and a new strategy for prevention and screening for cancer in the upper aerodigestive tract in East Asians. Keio J Med 2011; 59:115-30. [PMID: 21187698 DOI: 10.2302/kjm.59.115] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The ethanol in alcoholic beverages and the acetaldehyde associated with alcohol consumption are Group 1 human carcinogens (WHO, International Agency for Research on Cancer). The combination of alcohol consumption, tobacco smoking, the inactive heterozygous aldehyde dehydrogenase-2 genotype (ALDH2*1/*2) and the less-active homozygous alcohol dehydrogenase-1B genotype (ADH1B*1/*1) increases the risk of squamous cell carcinoma (SCC) in the upper aerodigestive tract (UADT) in a multiplicative fashion in East Asians. In addition to being exposed to locally high levels of ethanol, the UADT is exposed to a very high concentration of acetaldehyde from a variety of sources, including that as an ingredient of alcoholic beverages per se and that found in tobacco smoke; acetaldehyde is also produced by salivary microorganisms and mucosal enzymes and is present as blood acetaldehyde. The inefficient degradation of acetaldehyde by weakly expressed ALDH2 in the UADT may be cri! tical to the local accumulation of acetaldehyde, especially in ALDH2*1/*2 carriers. ADH1B*1/*1 carriers tend to experience less intense alcohol flushing and are highly susceptible to heavy drinking and alcoholism. Heavy drinking by persons with the less-active ADH1B*1/*1 leads to longer exposure of the UADT to salivary ethanol and acetaldehyde. The ALDH2*1/*2 genotype is a very strong predictor of synchronous and metachronous multiple SCCs in the UADT. High red cell mean corpuscular volume (MCV), esophageal dysplasia, and melanosis in the UADT, all of which are frequently found in ALDH2*1/*2 drinkers, are useful for identifying high-risk individuals. We invented a simple flushing questionnaire that enables prediction of the ALDH2 phenotype. New health appraisal models that include ALDH2 genotype, the simple flushing questionnaire, or MCV are powerful tools for devising a new strategy for prevention and screening for UADT cancer in East Asians.
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Yokoyama A, Tsutsumi E, Imazeki H, Suwa Y, Nakamura C, Yokoyama T. Polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 and the blood and salivary ethanol and acetaldehyde concentrations of Japanese alcoholic men. Alcohol Clin Exp Res 2010; 34:1246-56. [PMID: 20477767 DOI: 10.1111/j.1530-0277.2010.01202.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The effects of genetic polymorphism of aldehyde dehydrogenase-2 (ALDH2) on alcohol metabolism are striking in nonalcoholics, and the effects of genetic polymorphism of alcohol dehydrogenase-1B (ADH1B) are modest at most, whereas genetic polymorphisms of both strongly affect the susceptibility to alcoholism and upper aerodigestive tract (UADT) cancer of drinkers. METHODS We evaluated associations between ADH1B/ADH1C/ALDH2 genotypes and the blood and salivary ethanol and acetaldehyde levels of 168 Japanese alcoholic men who came to our hospital for the first time in the morning and had been drinking until the day before. RESULTS The ethanol levels in their blood and saliva were similar, but the acetaldehyde levels in their saliva were much higher than in their blood, probably because of acetaldehyde production by oral bacteria. Blood and salivary ethanol and acetaldehyde levels were both significantly higher in the subjects with the less active ADH1B*1/*1 genotype than in the ADH1B*2 carriers, but none of the levels differed according to ALDH2 genotype. Significant linkage disequilibrium was detected between the ADH1B and ADH1C genotypes, but ADH1C genotype did not affect the blood or salivary ethanol or acetaldehyde levels. High blood acetaldehyde levels were found even in the active ALDH2*1/*1 alcoholics, which were comparable with the levels of the inactive heterozygous ALDH2*1/*2 alcoholics with less active ADH1B*1/*1. The slope of the increase in blood acetaldehyde level as the blood ethanol level increased was significantly steeper in alcoholics with inactive heterozygous ALDH2*1/*2 plus ADH1B*2 allele than with any other genotype combinations, but the slopes of the increase in salivary acetaldehyde level as the salivary ethanol level increased did not differ between the groups of subjects with any combinations of ALDH2 and ADH1B genotypes. CONCLUSIONS The ADH1B/ALDH2 genotype affected the blood and salivary ethanol and acetaldehyde levels of nonabstinent alcoholics in a different manner from nonalcoholics, and clear effects of ADH1B genotype and less clear effects of ALDH2 were observed in the alcoholics. Alterations in alcohol metabolism as a result of alcoholism may modify the gene effects, and these findings provide some clues in regard to associations between the genotypes and the risks of alcoholism and UADT cancer.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan.
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Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: epidemiology, clinical findings, and prevention. Int J Clin Oncol 2010; 15:126-34. [PMID: 20224884 DOI: 10.1007/s10147-010-0056-7] [Citation(s) in RCA: 131] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Indexed: 12/20/2022]
Abstract
Both cigarette smoking and alcohol drinking are well-established risk factors for esophageal squamous cell carcinoma (ESCC), and the relationship of dose to cancer risk has already been described. Furthermore, the synergistic effect of these two factors has been reported. Our case-control study revealed the odds ratio of ESCC to be 50.1 for those who were both heavy smokers and heavy drinkers in comparison to people who neither drank nor smoked. In patients with ESCC, head and neck cancers as well as dysplastic lesions are frequently observed. Heavy smoking and heavy drinking are closely related to such multicentric carcinogenesis events in the upper aerodigestive tract (UADT), including the esophagus and head andneck region. Polymorphisms in acetaldehyde dehydrogenase 2 (ALDH2) are reported to be a key event in deciding individual susceptibility to UADT cancer. Patients with inactive ALDH2, in whom facial flushing is usually observed after the drinking of alcohol, are at high risk for ESCC as well as multiple UADT cancers. For the early detection of the disease, effective follow up using endoscopy with Lugol staining or narrow band imaging endoscopy is strongly recommended for high-risk populations, such as smokers, heavy drinkers, people with experience of flushing after the drinking of alcohol, and patients with UADT cancer.
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Oyama T, Kim YD, Isse T, Phuong PTT, Ogawa M, Yamaguchi T, Kinaga T, Yashima Y, Kim H, Kawamoto T. A pilot study on subacute ethanol treatment of ALDH2 KO mice. J Toxicol Sci 2007; 32:421-8. [PMID: 17965556 DOI: 10.2131/jts.32.421] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Aldh (aldehyde dehydrogenase ) 2 knockout (KO) mice have been generated in our laboratory. We evaluated the effects of subacute ethanol treatment on the survival rate, expression of Aldh1, Aldh2, Cytochrome P450 (Cyp) 1A1, Cyp2e1 and Cyp4b1 in wild (Aldh2+/+) mice (C57BL/6) and Aldh2 knock out (Aldh2-/-) mice. Physiological saline (0.3 mL/day) was administered to 4 Aldh2+/+ and 4 Aldh2-/- mice for 8 days as a control. Forty percent ethanol (0.3 mL/day; ethanol 2 g/kg/day) was then administered to 5 Aldh2+/+ and 9 Aldh2-/- mice for 8 days. Three mice of the ethanol administered Aldh2+/+ group and eight mice of the ethanol administered Aldh2-/- group died during the 8 days. The weights of mice were decreased by ethanol exposure to 85% and 74% in Aldh2+/+ and Aldh2-/- group, respectively. The survival rates of the ethanol administered Aldh2+/+ and Aldh2-/- group were 40 and 11%. Liver and pancreas disorder was revealed in the ethanol administered Aldh2+/+ and Aldh2-/- group in the results of serum chemical examination, immunohistochemical staining and western blot analysis. Cyp2e1 is more inducible to ethanol toxicity in Aldh2-/- mice compared with Aldh2+/+ mice when ethanol is administered according to the results of quantitative PCR.
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Woenckhaus M, Klein-Hitpass L, Grepmeier U, Merk J, Pfeifer M, Wild P, Bettstetter M, Wuensch P, Blaszyk H, Hartmann A, Hofstaedter F, Dietmaier W. Smoking and cancer-related gene expression in bronchial epithelium and non-small-cell lung cancers. J Pathol 2007; 210:192-204. [PMID: 16915569 DOI: 10.1002/path.2039] [Citation(s) in RCA: 123] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Tobacco smoking is the leading cause of lung cancer worldwide. Gene expression in surgically resected and microdissected samples of non-small-cell lung cancers (18 squamous cell carcinomas and nine adenocarcinomas), matched normal bronchial epithelium, and peripheral lung tissue from both smokers (n = 22) and non-smokers (n = 5) was studied using the Affymetrix U133A array. A subset of 15 differentially regulated genes was validated by real-time PCR or immunohistochemistry. Hierarchical cluster analysis clearly distinguished between benign and malignant tissue and between squamous cell carcinomas and adenocarcinomas. The bronchial epithelium and adenocarcinomas could be divided into the two subgroups of smokers and non-smokers. By comparison of the gene expression profiles in the bronchial epithelium of non-smokers, smokers, and matched cancer tissues, it was possible to identify a signature of 23 differentially expressed genes, which might reflect early cigarette smoke-induced and cancer-relevant molecular lesions in the central bronchial epithelium of smokers. Ten of these genes are involved in xenobiotic metabolism and redox stress (eg AKR1B10, AKR1C1, and MT1K). One gene is a tumour suppressor gene (HLF); two genes act as oncogenes (FGFR3 and LMO3); two genes are involved in matrix degradation (MMP12 and PTHLH); three genes are related to cell differentiation (SPRR1B, RTN1, and MUC7); and five genes have not been well characterized to date. By comparison of the tobacco-exposed peripheral alveolar lung tissue of smokers with non-smokers and with adenocarcinomas from smokers, it was possible to identify a signature of 27 other differentially expressed genes. These genes are involved in the metabolism of xenobiotics (eg GPX2 and FMO3) and may represent cigarette smoke-induced, cancer-related molecular targets that may be utilized to identify smokers with increased risk for lung cancer.
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Affiliation(s)
- M Woenckhaus
- Department of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D 93053 Regensburg, Germany.
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Yokoyama A, Tsutsumi E, Imazeki H, Suwa Y, Nakamura C, Yokoyama T. Contribution of the alcohol dehydrogenase-1B genotype and oral microorganisms to high salivary acetaldehyde concentrations in Japanese alcoholic men. Int J Cancer 2007; 121:1047-54. [PMID: 17471563 DOI: 10.1002/ijc.22792] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The less-active homozygous alcohol dehydrogenase-1B (ADH1B*1/*1) and inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) increase the risk of upper aerodigestive tract cancer (UADTC) in Japanese alcoholics. We evaluated associations between ADH1B/ALDH2 genotypes and the blood and salivary ethanol/acetaldehyde levels of 80 Japanese alcoholic men in the morning when they first visited our hospital after drinking the day before. Higher levels of ethanol persisted in the blood for longer periods in ADH1B*1/*1 carriers (n = 25) than in ADH1B*2 allele carriers after adjustment for the amount and time of the preceding alcohol consumption and body weight [median (25th-75th %): 20.5 mM (15.5-52.4) vs. below detection level (<DL) (<DL-6.4), p = 0.0003]. The ethanol levels in blood and saliva were similar, but the acetaldehyde levels in saliva were strikingly higher than in the blood, and were higher in ADH1B*1/*1 carriers than in ADH1B*2 allele carriers [47.4 muM (22.2-87.6) vs. 1.60 (<DL-26.3) in the saliva, p = 0.009]. The salivary acetaldehyde levels were correlated with salivary acetaldehyde production (r = 0.34, p = 0.002). The oral bacteria and yeast counts were correlated with salivary acetaldehyde production. Both the microorganisms counts and acetaldehyde production decreased after 3 weeks of abstinence, and the decreases were correlated (r = 0.35, p = 0.042). No effect of inactive ALDH2 (n = 12) on ethanol lingering the next morning was observed. In conclusion, the high salivary acetaldehyde levels in the alcoholics were partly attributable to prolonged ethanol exposure because of the less-active ADH1B and increased salivary acetaldehyde production as a result of oral microorganism overgrowth, and may explain their high risk for UADTC.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Alcoholism Center, Yokosuka, Kanagawa 239-0841, Japan.
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Yokoyama A, Kato H, Yokoyama T, Igaki H, Tsujinaka T, Muto M, Omori T, Kumagai Y, Yokoyama M, Watanabe H. Esophageal Squamous Cell Carcinoma and Aldehyde Dehydrogenase-2 Genotypes in Japanese Females. Alcohol Clin Exp Res 2006; 30:491-500. [PMID: 16499490 DOI: 10.1111/j.1530-0277.2006.00053.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Aldehyde dehydrogenase-2 (ALDH2) is the key enzyme for elimination of acetaldehyde, an established animal carcinogen produced after drinking. In persons with inactive ALDH2, the body fails to metabolize acetaldehyde rapidly, leading to excessive accumulation of acetaldehyde. Inactive heterozygous ALDH2 enhances the risk of esophageal squamous cell carcinoma (SCC) in Japanese male drinkers. METHODS We studied whether this is the case for women. The risk factors of esophageal SCC were examined in 52 Japanese women with esophageal SCC and 412 cancer-free Japanese women. RESULTS The increasing trend in cancer risk according to the quantity of alcohol consumption was significantly steeper in women with inactive heterozygous ALDH2 than in those with active ALDH2 [adjusted odds ratios (ORs) (95% confidence intervals (CIs)) per +7 U/wk increment of alcohol drinking were 3.91 (2.09-7.31) and 1.39 (0.92-2.09), respectively; p = 0.006 for difference in OR; 1 Ut = 22 g of ethanol]. The results obtained using an alcohol-flushing questionnaire were essentially comparable with those obtained by ALDH2 genotyping [adjusted ORs (95% CIs) per +7 U/wk increment of alcohol drinking were 3.94 (1.87-8.31) and 1.46 (0.96-2.23) in those with and without flushing, respectively; p = 0.021 for difference in OR]. The risk of esophageal cancer was markedly higher in heavy drinkers with ALDH2*1/*2 than in never/rare drinkers with ALDH2*1/*1 [adjusted OR (95% CI) = 59.1 (4.65-750)]. Other independent significant risk factors of esophageal SCC were smoking, a preference for hot food or drinks, and lower intake of green and yellow vegetables. CONCLUSIONS Japanese men and women shared several common risk factors of esophageal SCC, including drinking with inactive heterozygous ALDH2.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Alcoholism Center, Kanagawa, Japan.
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