Growth hormone regulation of hepatic drug-metabolizing enzymes in the mouse

Hepatic microsomal hexobarbital hydroxylase and aminopyrine N-demethylase activities increased in adult male mice following hypophysectomy to female-like levels, eliminating the normal sexually dimorphic pattern of these enzymes. Exogenous growth hormone replacement ( 0.08 I.U. 100 g body weight/day) re-established the lower masculine activities only when administered subcutaneously once every 12 hr. Enzyme activities remained elevated at female-like levels when the same total dose of growth hormone was infused continuously using osmotic pumps or was injected once every 6 hr. These data suggest that, despite the reversed orientation of sex differences in hepatic drug-metabolizing enzymes between rats and mice (i.e. higher enzyme activities in female mice and male rats), the basic hormonal regulatory axis is similar in the two species. Cyclic fluctuations of systemic growth hormone concentrations masculinize kinetic parameters of hepatic hexobarbital hydroxylase and aminopyrine N-demethylase in both species. Rats and mice differ in that these similar hormonal signals lower the apparent V_max in male mice, while markedly increasing the enzyme activities in male rats. It appears more likely, therefore, that species- and sex-specific differences in the total hepatic cytochrome P-450 isoenzyme populations produce the reversed sex-dependent pattern of hexobarbital hydroxylase and aminopyrine N-demethylase.