Evidence that the androgen receptor mediates sexual differentiation of mouse renal cytochrome P450 expression.
We have previously shown that sexual dimorphism in the expression of mouse renal cytochrome P450s is mediated by androgens, probably at a transcriptional level [Henderson, Scott, Yang & Wolf (1990), Biochem. J. 266, 675-681]. In the present study we show that this effect is already observed for most isoenzymes at only 2-3 weeks of age, as is the ability to induce or suppress expression with exogenous testosterone. The testosterone responsiveness did, however, exhibit age- as well as dose-dependency. Intriguingly, the effects of androgen took up to 8 days to become maximized, and the dose of testosterone needed to convert the female into the male phenotype was much higher than the circulating levels normally found in males. Studies using testicular feminized (Tfm) male mice, which carry an androgen receptor defect, showed them to have the female kidney cytochrome P450 phenotype, and these animals were not responsive to testosterone treatment. These data demonstrate the involvement of the androgen receptor in the regulation process. Taken together, our results indicate that the androgen receptor does not interact directly with the P450 genes, but initiates a cascade of events leading to the changes in cytochrome P450 gene expression. Significant differences were observed in the degree of sexual dimorphism in kidney P450 expression in other mammalian species. The significance of these findings in relation to the observed sexual dimorphism in other species is discussed.
Henderson
C J
CJ
Imperial Cancer Research Fund, Molecular Pharmacology Group, Edinburgh, U.K.
Wolf
C R
CR
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D007668:Kidney / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000201:enzymology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011944:Receptors, Androgen / Q000502:physiology*; D012727:Sex Characteristics; D012733:Sex Differentiation / Q000502:physiology*; D013045:Species Specificity; D013739:Testosterone / Q000097:blood
D011944:Receptors, Androgen; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System