title: B-Vitamin dependent methionine metabolism and alcoholic liver disease.
abstract: Convincing evidence links aberrant B-vitamin dependent hepatic methionine metabolism to the pathogenesis of alcoholic liver disease (ALD). This review focuses on the essential roles of folate and vitamins B6 and B12 in hepatic methionine metabolism, the causes of their deficiencies among chronic alcoholic persons, and how their deficiencies together with chronic alcohol exposure impact on aberrant methionine metabolism in the pathogenesis of ALD. Folate is the dietary transmethylation donor for the production of S-adenosylmethionine (SAM), which is the substrate for all methyltransferases that regulate gene expressions in pathways of liver injury, as well as a regulator of the transsulfuration pathway that is essential for production of glutathione (GSH), the principal antioxidant for defense against oxidative liver injury. Vitamin B12 regulates transmethylation reactions for SAM production and vitamin B6 regulates transsulfuration reactions for GSH production. Folate deficiency accelerates the experimental development of ALD in ethanol-fed animals while reducing liver SAM levels with resultant abnormal gene expression and decreased production of antioxidant GSH. Through its effects on folate metabolism, reduced SAM also impairs nucleotide balance with resultant increased DNA strand breaks, oxidation, hepatocellular apoptosis, and risk of carcinogenesis. The review encompasses referenced studies on mechanisms for perturbations of methionine metabolism in ALD, evidence for altered gene expressions and their epigenetic regulation in the pathogenesis of ALD, and clinical studies on potential prevention and treatment of ALD by correction of methionine metabolism with SAM.
authors.affiliation: Department of Internal Medicine, University of California Davis, Davis, CA 95616,USA. chhalsted@ucdavis.edu
authors.forename: Charles H
authors.initials: CH
authors.lastname: Halsted
mesh_terms: D044127:Epigenesis, Genetic; D000431:Ethanol / Q000633:toxicity; D005492:Folic Acid / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008108:Liver Diseases, Alcoholic / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008715:Methionine / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism; D014803:Vitamin B Complex / Q000378:metabolism*; D014804:Vitamin B Deficiency / Q000150:complications / Q000378:metabolism / Q000473:pathology
chemical_list: D014803:Vitamin B Complex; D000431:Ethanol; D012436:S-Adenosylmethionine; D005492:Folic Acid; D008715:Methionine