S-adenosylmethionine attenuates oxidative liver injury in micropigs fed ethanol with a folate-deficient diet.
BACKGROUND
To demonstrate a causative role for abnormal methionine metabolism in the pathogenesis of alcoholic steatohepatitis (ASH), we measured the preventive effects of supplementing folate deficient and ethanol containing diets in the micropig with S-adenosylmethionine (SAM), a metabolite that regulates methionine metabolism.


METHODS
Yucatan micropigs were fed folate-deficient diets as control, with ethanol at 40% of kcal, or with ethanol supplemented with SAM at 0.4 g/1000 kcal for 14 weeks. Histopathology, markers of liver injury, and regulatory enzymes were measured in terminal liver samples.


RESULTS
Among the ethanol group, livers showed hepatocellular necrosis together with increased levels of S-adenosylhomocysteine (SAH) and reduced levels of SAM and its ratio to SAH and glutathione (GSH), together with increased malondialdehyde plus hydroxynonenol (MDA + HNE) and nitrotyrosine (NT), transcripts and protein levels of cytochrome P4502E1 (CYP2E1), activity of NADPH oxidase, and activity and protein levels of inducible nitric oxide (iNOS). These findings were attenuated partially or completely to control levels by SAM supplementation of the ethanol diet.


CONCLUSIONS
The present results indicate that SAM supplementation attenuates ethanol induced liver injury through its effects on the expressions and activities of oxidative stress pathways, and are consistent with the concept that the pathogenesis of oxidative liver injury is regulated in part through altered hepatic methionine metabolism.
Villanueva
Jesus A
JA
Department of Internal Medicine, School of Medicine, University of California, Davis, CA 95616, USA.
Esfandiari
Farah
F
White
Mollie E
ME
Devaraj
Sridevi
S
French
Samuel W
SW
Halsted
Charles H
CH
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects*; D005234:Fatty Liver / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016014:Linear Models; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008715:Methionine / Q000378:metabolism; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects*; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature
D000431:Ethanol; D012436:S-Adenosylmethionine; D005492:Folic Acid; D008715:Methionine