Protective effect of pregnenolone-16 alpha-carbonitrile on acetaminophen-induced hepatotoxicity in hamsters.
Overdosage of acetaminophen (AA) is known to produce acute liver toxicity in both humans and laboratory animals. Hamsters are especially sensitive to the hepatotoxic effect of AA. In the present study, hamsters pretreated with pregnenolone-16 alpha-carbonitrile (PCN; 75 mg/kg, ip, daily for 4 days) were given a single dose of AA (350-1200 mg/kg, ip) and liver function was determined 24 hr later. Serum activities of alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) as well as histopathology were used as indices of hepatotoxicity. PCN pretreatment decreased AA-induced mortality. PCN dramatically decreased ALT (93-97%) and SDH (63-98%) activities relative to control values from hamsters treated with AA alone, and remarkably decreased hepatic centrilobular necrosis produced by AA. To investigate the mechanism of this protective effect, the biliary and urinary excretion of AA metabolites were measured for 1 hr after administration of AA (150 mg/kg, iv) in bile-duct-cannulated hamsters. PCN pretreatment resulted in increased urinary and biliary excretion of AA-glucuronide and decreased biliary excretion of AA-glutathione. Microsomes from PCN-pretreated hamsters produced less benzoquinoneimine intermediate than controls, as determined by the formation of AA-glutathione. In addition, hepatic UDP-glucuronic acid and UDP-glucuronosyltransferase were significantly increased in PCN-pretreated hamsters. In conclusion, PCN pretreatment protected against AA-induced hepatotoxicity. The mechanism of this protection appears to be due to decreased formation of the reactive metabolite by the cytochrome P450 pathway, and an increased detoxication by enhanced glucuronidation of AA.
Madhu
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Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66103.
Klaassen
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D000082:Acetaminophen / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D006224:Cricetinae; D003545:Cysteine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D004151:Dipeptides / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*
D004151:Dipeptides; C069746:acetaminophen cysteinylglycine; D011285:Pregnenolone Carbonitrile; D000082:Acetaminophen; C069744:acetaminophen cysteine; C037386:acetaminophen glucuronide; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; D003545:Cysteine; C045667:acetaminophen sulfate ester