INDUCTION OF MALE-SPECIFIC CYTOCHROME-P450 ISOZYMES IN FEMALE RATS BYOXANDROLONE

Oxandrolone (OXA) (5 alpha-androstan-2-oxa-17 alpha-methyl-17 beta-ol- 3-one) is a clinically useful, synthetic, anabolic androgen steroid ho rmone, OXA was administered to rats orally twice daily for 3 days at 7 5 mg/kg to study the effect on hepatic cytochrome P450 (P450) isozymes , Western blots were performed on the hepatic microsomal fraction and probed with isozyme-specific monoclonal antibodies, Microsomes were al so tested for catalytic activity in a testosterone metabolism assay. D ata from Western blots revealed that, in female rats, there were incre ased levels of two male-specific isozymes, P4502C11 and P4503A2, as we ll as P4503A1. In contrast, male rats showed little or no change in ex pression of these P450 isozymes after OXA treatment, The 6 beta-hydrox ylation of testosterone, which is catalyzed predominantly by P4503A1 a nd P4503A2, increased similar to 10-fold in female rats after treatmen t with OXA (from 0.05 +/- 0.01 to 0.52 +/- 0.05 nmol/min/mg protein), but only relatively small changes were seen in the male rats (from 1.0 2 +/- 0.05 to 1.38 +/- 0.07 nmol/min/mg protein). To investigate ii th e changes seen in P4503A1 and P4503A2 protein and activity were caused , at least in part, by an increase in mRNA levels, Northern blot analy sis was performed. P4503A2 mRNA was increased dramatically in the fema le rat liver after OXA treatment, but only small increases in P4503A1 mRNA were seen, This data indicate that OXA induces P450 isozymes in t he female but not in the male rat liver, probably through transcriptio nal activation, and some of these induced isozymes are male-specific.