title: Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease.
abstract: Fat accumulation (hepatic steatosis) in alcoholic and nonalcoholic fatty liver disease is a potentially pathologic condition which can progress to steatohepatitis (inflammation), fibrosis, cirrhosis, and carcinogenesis. Many clinically used drugs or some alternative medicine compounds are also known to cause drug-induced liver injury, which can further lead to fulminant liver failure and acute deaths in extreme cases. During liver disease process, certain cytochromes P450 such as the ethanol-inducible cytochrome P450-2E1 (CYP2E1) and CYP4A isozymes can be induced and/or activated by alcohol and/or high-fat diets and pathophysiological conditions such as fasting, obesity, and diabetes. Activation of these P450 isozymes, involved in the metabolism of ethanol, fatty acids, and various drugs, can produce reactive oxygen/nitrogen species directly and/or indirectly, contributing to oxidative modifications of DNA/RNA, proteins and lipids. In addition, aldehyde dehydrogenases including the mitochondrial low Km aldehyde dehydrogenase-2 (ALDH2), responsible for the metabolism of acetaldehyde and lipid aldehydes, can be inactivated by various hepatotoxic agents. These highly reactive acetaldehyde and lipid peroxides, accumulated due to ALDH2 suppression, can interact with cellular macromolecules DNA/RNA, lipids, and proteins, leading to suppression of their normal function, contributing to DNA mutations, endoplasmic reticulum stress, mitochondrial dysfunction, steatosis, and cell death. In this chapter, we specifically review the roles of the alcohol-metabolizing enzymes including the alcohol dehydrogenase, ALDH2, CYP2E1, and other enzymes in promoting liver disease. We also discuss translational research opportunities with natural and/or synthetic antioxidants, which can prevent or delay the onset of inflammation and liver disease.
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA. Electronic address: bj.song@nih.gov.
authors.forename: Byoung-Joon
authors.initials: BJ
authors.lastname: Song
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Akbar
authors.affiliation: Department of Molecular Medicine, Ewha Womans University School of Medicine, Seoul, South Korea.
authors.forename: Inho
authors.initials: I
authors.lastname: Jo
authors.affiliation: Biochemistry and Molecular Pathology in Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Hardwick
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Abdelmegeed
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism*; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000201:enzymology* / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology* / Q000378:metabolism*
chemical_list: D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1
keywords: ALDH2; Alcohol-metabolizing enzymes; CYP2E1; Liver disease; Mitochondrial dysfunction; Nitroxidative stress; Posttranslational modifications