title: Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors.
abstract: Alcohol-induced liver injury (ALI) has been associated with, among other molecular changes, abnormal hepatic methionine metabolism, resulting in decreased levels of S-adenosylmethionine (SAM). Dietary methyl donor supplements such as SAM and betaine mitigate ALI in animal models; however, the mechanisms of protection remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress. We hypothesized that the protective action of methyl donors is mediated by an effect on the oxidative metabolism of alcohol in the liver. Male C57BL/6J mice were administered a control high-fat diet or diet enriched in methyl donors with or without alcohol for 4 weeks using the enteral alcohol feeding model. As expected, attenuation of ALI and an increase in reduced glutathione:oxidized glutathione ratio were achieved with methyl donor supplementation. Interestingly, methyl donors led to a 35% increase in blood alcohol elimination rate, and while there was no effect on alcohol metabolism in the stomach, a profound effect on liver alcohol metabolism was observed. The catalase-dependent pathway of alcohol metabolism was induced, yet the increase in CYP2E1 activity by alcohol was blunted, which may be mitigating production of oxidants. Additional factors contributing to the protective effects of methyl donors in ALI were increased activity of low- and high-K(m) aldehyde dehydrogenases leading to lower hepatic acetaldehyde, maintenance of the efficient mitochondrial energy metabolism, and promotion of peroxisomal beta-oxidation. Profound changes in alcohol metabolism represent additional important mechanism of the protective effect of methyl donors in ALI.
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Powell
authors.forename: Blair U
authors.initials: BU
authors.lastname: Bradford
authors.forename: Christopher Patrick
authors.initials: CP
authors.lastname: Craig
authors.forename: Masato
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Takeki
authors.initials: T
authors.lastname: Uehara
authors.forename: Thomas M
authors.initials: TM
authors.lastname: O'Connell
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
authors.forename: Stepan
authors.initials: S
authors.lastname: Melnyk
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Koop
authors.forename: Lisa
authors.initials: L
authors.lastname: Bleyle
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D001622:Betaine / Q000008:administration & dosage*; D002374:Catalase / Q000096:biosynthesis; D002492:Central Nervous System Depressants / Q000493:pharmacokinetics / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004041:Dietary Fats / Q000008:administration & dosage; D019587:Dietary Supplements; D004790:Enzyme Induction / Q000187:drug effects; D000431:Ethanol / Q000493:pharmacokinetics / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000008:administration & dosage*
chemical_list: D002492:Central Nervous System Depressants; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004041:Dietary Fats; D000431:Ethanol; D001622:Betaine; D012436:S-Adenosylmethionine; D002374:Catalase; D019392:Cytochrome P-450 CYP2E1; D000444:Aldehyde Dehydrogenase; D005978:Glutathione