Effect of the Tfin Locus on the Hepatic Ethylmorphine JV-Demethylase System in Mice*

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Abstract
Certain androgen specific and nonspecific responses were investigated in mouse liver. The hepatic cytochrome P-450-dependent ethylmorphine N-demethylase system of androgen-insensitive (Tfm/Y) mice and normal littermates was evaluated in response to sex steroids, phenobarbital and 3-methylcholanthrene. Microsomes from normal male (+/Y) mice had the greatest level of cytochrome P-450, but exhibited a lower Vmax and higher Km for ethylmorphine N-demethylation than normal female (+/+), carrier female (Tfm/+), and Tfm/Y mice. Androgen treatment decreased ethylmorphine N-demethylase activity of +/+ and +/Y mice but had no effect in animals with a defective androgen receptor (Tfm/Y). Estradiol decreased activity in both Tfm/Y and +/Y mice. Cytochrome P-450 content was decreased by testosterone only in +/+ mice while estradiol decreased levels in all mice. The progestins, cyproterone acetate and progesterone, increased N-demethylase activity and cytochrome P-450 content in all animals, while medroxyprogesterone acetate was without effect. In contrast to their differential effects on N-demethylase activity, testosterone, estradiol and progestin treatment increased microsomal protein content in all mice irrespective of genotype. Normal induction patterns of the hepatic microsomal ethylmorphine N-demethylase system were observed in +/+, +/Y and Tfm/Y mice after phenobarbital treatment, and in benzo(.alpha.)pyrene hydroxylase activity and cytochrome P1-450 content after treatment with 3-methylcholanthrene. Androgens apparently stimulate liver wt and hepatic microsomal protein content by a mechanism independent of the androgen receptor. Androgen-induced changes in ethylmorphine-N-demethylase activity may require a functional androgen receptor in liver. The Tfm locus probably does not influence the response of hepatic drug-metabolizing enzymes to estrogen, progestins, phenobarbital, or 3-methylcholanthrene. The relative biological activity of progestins on liver apparently does not correlate with the progestational or androgenic actions of these steroids.