Detection of covalently bound halothane metabolites in the hypoxic rat model for halothane hepatotoxicity.

Using a non-radiometric technique, halothane metabolites have been shown to covalently bind to rat hepatic tissue with the production of a lesion. The conditions required for optimizing the lesion (hypoxia and biotransformation enzyme induction) also optimizes the binding of fluorinated halothane residues to hepatic tissue. The maximal binding of fluorinated halothane residues to the liver of rats precedes the development of the hepatic lesion. Female rats, which are resistant to the halothane initiated lesion, have one-third as much covalently bound halothane residue. Biotransformation inhibitors (SKF-525A, metyrapone), which inhibited lesion formation, also inhibit the covalent binding of halothane to hepatic tissue. Cystamine and cysteine, sulfhydryl agents which can inhibit hepatic lesion development when administered four hr after halothane exposure, also suppressed the amount of halothane metabolites covalently bound to hepatic tissue. Using this non-radioactive method for measuring the covalent binding of halothane to hepatic tissue, it appears that the bioactivation of halothane was a necessary event for the appearance of a halothane initiated hepatic lesion.