In vivo and in vitro hepatotoxicity and metabolism of acetaminophen in Syrian hamsters.
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.
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
D000082:Acetaminophen; D008748:Methylcholanthrene; D007064:L-Iditol 2-Dehydrogenase; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D010634:Phenobarbital