title: Major differences in the specificity and regulation of mouse renal cytochrome P-450-dependent monooxygenases. A comparison of xenobiotic and endogenous substrates.
abstract: In the present study we have investigated the influence of sex on the specificity of mouse renal microsomes toward endogenous and xenobiotic substrates. Renal microsomes from C3H/HeJ mice were characterized by the following: a 4- to 5-fold male predominance in cytochrome P-450 concentration; a difference between male and female renal microsomes in the absorption maximum for the reduced P-450 . CO complex, 450 and 452 nm, respectively; a lack of a sex difference in lauric acid 12-hydroxylase activity; an 18-fold sex difference (M greater than F) in progesterone 16 alpha-hydroxylase activity; and 8- to 10-fold sex differences (M greater than F) in progesterone 15 alpha-hydroxylase, dimethylnitrosamine demethylase, and lauric acid 11-hydroxylase activities. Treatment of female mice with testosterone propionate selectively induced lauric acid 11-hydroxylase and dimethylnitrosamine demethylase activities 8- and 14-fold, respectively, but had no effect on progesterone 15 alpha- and 16 alpha-hydroxylase activities or on the high female rate of lauric acid 12-hydroxylation. Inhibition studies conducted with male mouse renal microsomes revealed that of the substrates examined, only testosterone inhibited the 15 alpha- and 16 alpha-hydroxylations of progesterone in vitro. In addition, progesterone 15 alpha-hydroxylase was distinguished from 16 alpha-hydroxylase by the greater degree of testosterone inhibition (68 and 44%, respectively) and by sensitivity to metyrapone inhibition. Mouse renal cytochrome P-450 heterogeneity is indicated by the selective effects of androgen induction and metyrapone inhibition. Moreover, distinct modes of regulation are observed between the isozymes involved in steroid hydroxylation and those which catalyze the 11- and 12-hydroxylations of lauric acid in mouse renal microsomes.
mesh_terms: D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D005260:Female; D007668:Kidney / Q000201:enzymology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008861:Microsomes / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000032:analysis; D010089:Oxidoreductases, N-Demethylating / Q000032:analysis; D010105:Oxygenases / Q000032:analysis*; D012737:Sex Factors; D039181:Steroid 16-alpha-Hydroxylase; D013379:Substrate Specificity; D013739:Testosterone / Q000494:pharmacology
chemical_list: D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D019392:Cytochrome P-450 CYP2E1; D039181:Steroid 16-alpha-Hydroxylase; D010089:Oxidoreductases, N-Demethylating