The shark bile salt 5 beta-scymnol abates acetaminophen toxicity, but not covalent binding.
Acetaminophen (APAP) toxicity involves both arylative and oxidative mechanisms. The shark bile salt, 5 beta-scymnol (5beta-S), has been demonstrated to act as an antioxidant and free radical scavenger in vitro. To determine if 5beta-S protects against either APAP-induced hepatic or renal toxicity, 3-4-month-old male Swiss Laca mice were given APAP (500 mg/kg), and 5beta-S (100 mg/kg) was given at 0 and 2 h after APAP. Plasma SDH at 12 h after APAP alone was 1630 U/l and BUN was 19 mg/dl versus 20 U/l and 10 mg/dl, respectively, in controls. Either simultaneous or 2 h delayed treatment with 5beta-S significantly decreased the APAP-induced SDH increase while only the simultaneous pretreatment prevented the BUN elevation. 5beta-S alone did not increase liver glutathione content. Western analysis of APAP covalent binding using anti-APAP antibodies indicated the 5beta-S did not alter protein arylation either qualitatively or quantitatively. These results suggest that 5beta-S treatment did not impair APAP activation and are consistent with 5beta-S protection that likely results from its antioxidant activity.
Slitt
Angela Lucas
AL
Toxicology Program, Department of Pharmaceutical Sciences, University of Connecticut, Storrs, 06269-2092, USA. aslitt@kumc.edu
Naylor
Lee
L
Hoivik
J
J
Manautou
Jose E
JE
Macrides
Theo
T
Cohen
Steven D
SD
D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control; D002777:Cholestanols / Q000378:metabolism / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D007202:Indicators and Reagents; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D012754:Sharks / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000378:metabolism
D000975:Antioxidants; D001647:Bile Acids and Salts; D002777:Cholestanols; D007202:Indicators and Reagents; D000082:Acetaminophen; C074469:scymnol; D007770:L-Lactate Dehydrogenase; D013385:Succinate Dehydrogenase; D005978:Glutathione