Halothane Hepatotoxicity

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Abstract
Pretreatment of rats with the potent mixed-function oxidase system inducer, Aroclor 1254 (150 .mu.mol/kg for 7 days), provides a model system for the study of halothane hepatotoxicity. Within 2 h of the end of anesthesia (0.85% for 5 h), values of the serum transaminases (SGOT [serum glutamic-oxaloacetic transaminase] and SGPT [serum glutamic pyruvic transaminase] were increased to above normal and morphologic injury was recognized in centrilobular parenchymal cells of animals pretreated with Aroclor 1254. Necrosis of the centrilobular hepatocytes was prominent within 24 h. Ultrastructural examination of hepatic tissue at intervals after anesthesia indicated that the injury primarily involved the endoplasmic reticulum (ER), progressing from dispersion of the rough ER to vacuolization of the rough ER and coalescence of the smooth components of this membranous system into tubular aggregates. These changes were preceded by selective deactivation of the mixed-function oxidase components, cytochrome P-450 and zoxazolamine hydroxylase, and early transient increases in conjugated dienes of lipids. Although pretreatment with Aroclor 1254 potentiated halothane hepatotoxicity, neither covalent binding of labeled halothane to liver proteins nor excretion of water-soluble labeled metabolites in urine was enhanced 24 h after i.p. administration of a low non-hepatotoxic or high hepatotoxic dose of 14C-1-labeled halothane (10 and 10,000 .mu.mol/kg, respectively). The toxic pathway(s) for the biotransformation of halothane probably do not involve increased production of water-soluble or protein-bound metabolites.