An animal model of halothane hepatotoxicity: roles of enzyme induction and hypoxia.
Exposure of phenobarbital-pretreated male Sprague-Dawley rats to halothane, 1 per cent, for two hours under conditions of hypoxia (FIO2 0.14) resulted in extensive centrilobular necrosis within 24 hours. Accompanying the morphologic damage were an increase in serum glutamic pyruvic transminase (SGPT) and a decrease in hepatic microsomal cytochrmoe P-450. Glutathione levels in the liver were unchanged. Phenobarbital-pretreated rats anesthetized with halothane, 1 per cent, at FIO2 0.21 had only minor morphologic changes at 24 hours. Hepatic injury was not apparent in any non-phenobarbital-induced rat or in any induced animal exposed to ether at FIO2 0.10 or to halothane at FIO2 0.99. There was a 2.6-fold increase in the 24-hour urinary excretion of fluoride in those rats in which extensive centrilobular necrosis developed. The in-vivo covalent binding to lipids of 14C from 14C-halothane also was increased markedly when 14C-halothane was administered intraperitoneally to phenobarbital-induced rats maintained hypoxic (FIO2 0.14) for two hours. These results support the authors' hypothesis that halothane is metabolized to hepatotoxic intermediates by a reductive or non-oxygen-dependent cytochrome P-450-dependent pathway. This animal model of halothane-induced hepatotoxicity may be clinically relevant. A decrease in hepatic blood flow during halothane anesthesia may decrease the PO2 available to hepatocytes and thus direct the metabolism of halothane along its reductive, hepatotoxic pathway.
D000410:Alanine Transaminase / Q000378:metabolism*; D000769:Anesthesia, Inhalation; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005459:Fluorides / Q000652:urine; D005978:Glutathione / Q000378:metabolism; D006221:Halothane / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D000860:Hypoxia / Q000150:complications* / Q000201:enzymology / Q000378:metabolism; D007274:Injections, Intraperitoneal; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008102:Liver Circulation; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009336:Necrosis; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats
D003577:Cytochrome P-450 Enzyme System; D000410:Alanine Transaminase; D005978:Glutathione; D005459:Fluorides; D006221:Halothane; D010634:Phenobarbital