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TERRY R. BROWN, FRANK E. GREENE, LESLIE P. BULLOCK, C. WAYNE BARDIN, Effect of the Tfin Locus on the Hepatic Ethylmorphine JV-Demethylase System in Mice, Endocrinology, Volume 103, Issue 4, 1 October 1978, Pages 1374–1382, https://doi.org/10.1210/endo-103-4-1374
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The present study further investigates certain androgen specific and nonspecific responses 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 Vma]t 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). By contrast, estradiol decreased activity in both Tfm/Y and +/Y mice. Cytochrome P-450 content was decreased by testosterone only in +/+ mice whereas estradiol decreased levels in all mice. The progestins, cyproterone acetate and progesterone, increased N-demethylase activity and cytochrome P-450 content in all animals, whereas 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. In addition, 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(α)pyrene hydroxylase activity and cytochrome P1-450 content after treatment with 3-methylcholanthrene.
These observations suggest that: 1) androgens stimulate liver weight and hepatic microsomal protein content by a mechanism independent of the androgen receptor; 2) androgen-induced changes in ethylmorphine- N-demethylase activity require a functional androgen receptor in liver; 3) the Tfm locus does not influence the response of hepatic drug-metabolizing enzymes to estrogen, progestins, phenobarbital, or 3-methylcholanthrene; 4) the relative biological activity of progestins on liver does not correlate with the progestational or androgenic actions of these steroids.
