STRAIN DIFFERENCES IN AGE-ASSOCIATED CHANGE IN TESTOSTERONE 6-BETA-HYDROXYLATION IN WISTAR AND DARK AGOUTI RATS

This study examines strain differences in testosterone (T)-hydroxylati ons between Wistar and Dark Agouti (DA) rats of both genders. The DA r at, an animal model, is a poor metabolizer of such drugs as debrisoqui ne, which are metabolized by cytochrome P450 (CYP) 2D. T-16 alpha-, 2 alpha-hydroxylations, which are linked to CYP2C11, were catalyzed at s imilar rates by the microsomes of both strains. In contrast, the liver microsomes from mature male DA rats catalyzed T-6 beta-hydroxylation, the CYP3A mediated activity, at higher rates (similar to 2-fold) than Wistar rat liver microsomes did. There was no difference between imma ture male DA and Wistar rats for T-6 beta-hydroxylation, indicating th at the activity in male DA rat increases with maturation. Polyclonal a ntibodies raised against rat liver microsomal CYP3A2 and a CYP3A inhib itor, troleandomycin (TAO), effectively inhibited T-6 beta-hydroxylati on by liver microsomes from both strains of rats. The level of T-6 bet a- hydroxylation activity correlated well with the amount of CYP3A pro tein in the microsomes in mature as well as in immature male and femal e Wistar and DA rats. Northern blot analysis repeatedly indicated that the cellular contents of CYP3A2 mRNA are slightly (similar to 20%) hi gher in the liver of mature DA rats than in that of mature Wistar rats . These results indicate that the increased levels of CYP3A are respon sible for the increased T-6 beta-hydroxylation activity and protein in DA rat. (C) 1997 Elsevier Science B.V.