title: In vivo and in vitro hepatotoxicity and metabolism of acetaminophen in Syrian hamsters.
abstract: The purpose of this investigation was to correlate the in vitro and in vivo toxicity of the hepatotoxicant, acetaminophen. Hamsters were pretreated with either phenobarbital (70 mg/kg) or 3-methylcholanthrene (20 mg/kg) or an appropriate vehicle for 3 days. In non-pretreated hamsters, single doses of acetaminophen (200-400 mg/kg i.p.) caused elevations in serum alanine aminotransferase and sorbitol dehydrogenase activities in a dose-related manner. 3-Methylcholanthrene significantly potentiated, while phenobarbital significantly reduced acetaminophen-induced elevations in serum liver enzyme activities. Both phenobarbital and 3-methylcholanthrene significantly reduced acetaminophen plasma T1/2 while only 3-methylcholanthrene increased APAP clearance. Phenobarbital pretreatment increased the urinary excretion of APAP-glucuronide. Exposure of isolated hepatocytes to acetaminophen (0.01-2.0 mM) resulted in concentration-related decreases in hepatocyte viability. Cells from 3-methylcholanthrene-pretreated hamsters were more markedly susceptible to acetaminophen toxicity than cells isolated from non-induced animals. Hepatocytes isolated from phenobarbitol pretreated animals were slightly but significantly more susceptible to acetaminophen toxicity than cells from control animals. Hepatocytes isolated from 3-methylcholanthrene pretreated animals had increased formation of an acetaminophen-glutathione conjugate compared to control. Pre-treatment with either phenobarbital or 3-methylcholanthrene enhanced glucuronidation of acetaminophen in vitro. These data demonstrate a lack of correlation between in vivo hepatotoxicity and in vitro cytotoxicity in that phenobarbital pre-treatment protected hamsters from acetaminophen-induced liver toxicity, but failed to protect hepatocytes exposed to acetaminophen in vitro.
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D008748:Methylcholanthrene / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology
chemical_list: D000082:Acetaminophen; D008748:Methylcholanthrene; D007064:L-Iditol 2-Dehydrogenase; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D010634:Phenobarbital