Sex Differences in the Kinetic Constants of Ethylmorphine Demethylation and Type I Binding to Hepatic Microsomal Cytochrome P-450 in Mice. The Influence of Castration and Testosterone

Abstract

1. In the CPB-SE mouse strain sex differences were observed in the K_m and V_max of ethylmorphine demethylation and in the ΔA_max of its type I binding to cytochrome P-450. In the CPB-V strain a small sex difference in the V_max of the demethylation was found, whereas K_s and ΔA_max, of type I binding differed considerably.

2. Testosterone pre-treatment of female CPB-SE mice abolished all sex differences, as did castration of males, except in V_max, which was partially decreased. In the CPB-V strain testosterone pre-treatment of females abolished sex differences in type I binding, but had no effect on ethylmorphine demethylation.

3. K_m values exceeded the corresponding K_s in all cases and sex differences in ΔA_max far exceeded those in V_max. It is concluded that the K_m is determined not only by the K_s of type I binding and the reduction rate of the type I complex between ethylmorphine and cytochrome P-450. The larger sex differences in ΔA_max as compared with V_max may be attributable to type I binding of ethylmorphine to cytochrome P-450 subspecies not involved in its demethylation.