Age and gender influence halothane-associated hepatotoxicity in strain 13 guinea pigs

The factors of age and gender, which have been linked to development of fulminant halothane hepatitis in humans, were evaluated in a guinea pig model of acute halothane-associated hepatotoxicity. Since nitrous oxide is commonly coadministered with halothane and has been shown to exacerbate halothane-associated liver injury in rats; this combination of anesthetics was also evaluated in guinea pigs. Male and female strain 13 guinea pigs (300-1000 g) were exposed to 1% v/v halothane and 39% O2 for 4 h with a balance of either 60% N2 or 60% N2O. Both animal age, as determined by body weight, and gender proved to be factors in the model with older (approximately 6.2 +/- 1.0 month) guinea pigs of both sexes, demonstrating significantly greater elevations in plasma ALT and a greater incidence of centilobular necrosis versus younger (approximately 3.1 +/- 0.6 month) animals. Older females showed a greater hepatotoxic response than older males. There were no significant differences in halothane plasma metabolite levels between older and younger animals of either gender. The addition of nitrous oxide affected neither plasma concentrations of halothane metabolites nor the degree of resultant hepatic injury. Older (approximately 5-6 month) male guinea pigs, from a strain (inbred Hartley) previously shown to be resistant to the halothane lesion, did not develop centrilobular necrosis following halothane exposure even though they generated plasma metabolite concentrations equivalent to those generated by strain 13 animals. The lack of differences in the biotransformation of halothane between groups indicates that other intrinsic factors must be involved in the observed variations in susceptibility to hepatic injury.