Temporal study of acetaminophen (APAP) and S-adenosyl-L-methionine (SAMe) effects on subcellular hepatic SAMe levels and methionine adenosyltransferase (MAT) expression and activity.
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.
Brown
J Michael
JM
Department of Pharmacology, Physiology, and Toxicology, 1 John Marshall Drive, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
Ball
John G
JG
Hogsett
Amy
A
Williams
Tierra
T
Valentovic
Monica
M
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*
D020011:Protective Agents; D000082:Acetaminophen; D012436:S-Adenosylmethionine; D008716:Methionine Adenosyltransferase
Toxicol Sci. 2003 Nov;76(1):229-36
12944590
Oral Surg Oral Med Oral Pathol. 1981 Apr;51(4):385-9
6940075
Hepatology. 1991 Sep;14(3):528-33
1874498
Chem Biol Interact. 1984 Mar;48(3):349-66
6713598
Clin Invest Med. 2005 Jun;28(3):132-9
16021987
World J Gastroenterol. 2007 Oct 7;13(37):4947-54
17854136
J Gastroenterol Hepatol. 2008 Mar;23 Suppl 1:S73-7
18336669
Toxicol Lett. 2004 Dec 30;154(3):165-74
15501608
Curr Protoc Cell Biol. 2001 Nov;Chapter 3:3.10.1-3.10.19
18228353
Toxicol Lett. 2008 Apr 1;177(3):188-97
18313239
J Pharmacol Exp Ther. 1985 Mar;232(3):864-72
3973835
J Pharmacol Exp Ther. 2005 Feb;312(2):509-16
15466245
Br J Pharmacol Chemother. 1966 Mar;26(3):606-14
5959211
Hepatology. 1992 Feb;15(2):297-301
1735533
Proc Natl Acad Sci U S A. 1984 Mar;81(5):1327-31
6424115
Int J Vitam Nutr Res. 1994;64(1):41-6
8200748
Pharmacoepidemiol Drug Saf. 2006 Jun;15(6):398-405
16294364
J Biol Chem. 1985 Oct 25;260(24):13035-40
2932433
FASEB J. 2001 May;15(7):1248-50
11344103
Chem Biol Interact. 2005 Sep 10;156(1):13-23
16098496
Chem Res Toxicol. 1993 Jul-Aug;6(4):511-8
8374050
Gastroenterology. 2003 Apr;124(4):940-8
12671891
Anal Biochem. 2003 Aug 1;319(1):13-20
12842102
Toxicology. 2008 Feb 3;244(1):25-34
18068290
Biochem Mol Biol Int. 1996 Nov;40(4):807-14
8950039
Int J Biochem Cell Biol. 2000 Apr;32(4):391-5
10762064
J Chromatogr B Biomed Sci Appl. 2001 Oct 5;762(1):59-65
11589459
Mol Toxicol. 1987-1988 Fall;1(4):301-11
3509688
Biochem J. 2004 Apr 1;379(Pt 1):183-90
14674884
FASEB J. 2004 May;18(7):914-6
15033934
J Biochem Mol Toxicol. 2004;18(6):361-8
15674847
Am J Clin Nutr. 2007 Jul;86(1):14-24
17616758
J Nutr. 2001 Nov;131(11):2811-8
11694601
J Nutr Biochem. 1990 May;1(5):228-37
15539209
N Engl J Med. 1988 Dec 15;319(24):1557-62
3059186
Curr Protoc Toxicol. 2004 May;Chapter 2:Unit2.10
23045105
Biochem J. 1991 Feb 15;274 ( Pt 1):225-9
2001237
Am J Clin Nutr. 2002 Nov;76(5):1148S-50S
12418492
Mol Pharmacol. 1980 Nov;18(3):536-42
7464816
Proc Natl Acad Sci U S A. 2001 May 8;98(10):5560-5
11320206
Trends Genet. 1997 Feb;13(2):51-2
9055605
J Pharmacol Exp Ther. 1973 Oct;187(1):211-7
4746329
Nitric Oxide. 2002 Mar;6(2):160-7
11890740
Arch Biochem Biophys. 1974 Dec;165(2):774-9
4441103
Hepatology. 1990 Feb;11(2):165-72
2307395
Biochemistry. 1983 Mar 29;22(7):1636-41
6849873
Chem Biol Interact. 1990;75(2):201-11
2369786
Am J Physiol. 1998 Jul;275(1):G14-21
9655679
Biochem Pharmacol. 2007 Aug 1;74(3):521-31
17574213
Hepatology. 2002 Jun;35(6):1381-91
12029623
Semin Liver Dis. 1998;18(4):331-43
9875552
Toxicol Appl Pharmacol. 2006 Mar 1;211(2):157-65
16081117
Biochem Pharmacol. 1979 Dec 15;28(24):3567-71
533559
Hepatology. 1992 Oct;16(4):1022-7
1398482
J Pharmacol Exp Ther. 2008 Jan;324(1):8-14
17906064
J Pharmacol Exp Ther. 2007 Jan;320(1):99-107
17065366