title: Temporal study of acetaminophen (APAP) and S-adenosyl-L-methionine (SAMe) effects on subcellular hepatic SAMe levels and methionine adenosyltransferase (MAT) expression and activity.
abstract: Acetaminophen (APAP) is the leading cause of drug induced liver failure in the United States. Previous studies in our laboratory have shown that S-adenosyl methionine (SAMe) is protective for APAP hepatic toxicity. SAMe is critical for glutathione synthesis and transmethylation of nucleic acids, proteins and phospholipids which would facilitate recovery from APAP toxicity. SAMe is synthesized in cells through the action of methionine adenosyltransferase (MAT). This study tested the hypothesis that total hepatic and subcellular SAMe levels are decreased by APAP toxicity. Studies further examined MAT expression and activity in response to APAP toxicity. Male C57BL/6 mice (16-22 g) were treated with vehicle (Veh; water 15 ml/kg ip injections), 250 mg/kg APAP (15 ml/kg, ip), SAMe (1.25 mmol/kg) or SAMe administered 1h after APAP injection (SAMe and SAMe+APAP). Hepatic tissue was collected 2, 4, and 6h after APAP administration. Levels of SAMe and its metabolite S-adenosylhomocysteine (SAH) were determined by HPLC analysis. MAT expression was examined by Western blot. MAT activity was determined by fluorescence assay. Total liver SAMe levels were depressed at 4h by APAP overdose, but not at 2 or 6h. APAP depressed mitochondrial SAMe levels at 4 and 6h relative to the Veh group. In the nucleus, levels of SAMe were depressed below detectable limits 4h following APAP administration. SAMe administration following APAP (SAMe+APAP) prevented APAP associated decline in mitochondrial and nuclear SAMe levels. In conclusion, the maintenance of SAMe may provide benefit in preventing damage associated with APAP toxicity.
authors.affiliation: Department of Pharmacology, Physiology, and Toxicology, 1 John Marshall Drive, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Brown
authors.forename: John G
authors.initials: JG
authors.lastname: Ball
authors.forename: Amy
authors.initials: A
authors.lastname: Hogsett
authors.forename: Tierra
authors.initials: T
authors.lastname: Williams
authors.forename: Monica
authors.initials: M
authors.lastname: Valentovic
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D004347:Drug Interactions; D042541:Intracellular Space / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008716:Methionine Adenosyltransferase / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D012436:S-Adenosylmethionine / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D020011:Protective Agents; D000082:Acetaminophen; D012436:S-Adenosylmethionine; D008716:Methionine Adenosyltransferase
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