Bioactivation and hepatotoxicity of ²H/³H halothane

Results in rats suggest that scission of the C-H bond is not a determining factor in the hepatotoxicity of halothane, since no apparent differences in liver injury were observed between halothane and d-halothane. Also, no significant changes between halothane and d-halothane were found in the levels of those metabolites produced during the reductive biotransformation of halothane (F^- and the volatile metabolites, CDE and CTE). However, deuterium substitution markedly reduced the oxidative biotransformation of halothane, as evidenced by the 60% decrease in debromination. The covalent binding data also indicate that scission of the C-H bond does not occur during reductive bioactivation of halothane, since the ³H was retained under reductive conditions. The differences in stoichiometry of the binding of ³H-halothane and ¹⁴C-halothane are interesting and may indicate that different reactive intermediates exist for binding to lipid or protein and/or for O₂ or N₂ atmospheres, or reflect isotope effects or isotope exchange reactions. However, binding of ³H-halothane equivalents may be a useful marker for reductive biotransformation of halothane and its associated toxicity.