COMPARISON OF THE BIOTRANSFORMATION AND HEPATOTOXICITY OF HALOTHANE AND DEUTERATED HALOTHANE

Abstract

To investigate the effect of deuterium substitution on the biotransformation and hepatotoxicity of halothane, male, phenobarbital-pretreated rats were exposed for 2 h to 1% halothane or deuterated halothane (d-halothane) delivered in 14% O2 85% N2. The exposures were performed at mildly hypoxic conditions (14% O2) since it was previously established that the decreased O2 tension promotes both the reductive metabolism of halothane and halothane-induced liver injury. At the end of anesthesia or at 24 h, the rats were sacrificed so that blood, liver and urine samples could be obtained for measurement of metabolites and assessment of liver damage. Deuterium substitution did not affect the levels of reductive metabolites of halothane (fluoride, CF3CH2Cl and CF2CHCl) nor did it alter the degree of hepatotoxicity as assessed by serum glutamic-pyruvic transaminase levels and morphological examination. The levels of oxidative metabolites (CF3COOH and bromide) were significantly reduced at the end of anesthesia and at 24 h. Halothane-induced hepatotoxicity is initiated by reactive intermediates formed during its reductive metabolism and cleavage of the C-H bond is not involved in this pathway. The oxidative biotransformation of halothane proceeds by an O2 insertion reaction at the C-H bond. The increased stability of the C-D bond explains the reduction in oxidative metabolites observed after exposure to d-halothane.