17-Hydroexemestane: A Potent Inhibitor of CYP19 (Aromatase) and Substrate of CYP3A

17-hydroexemestane is the major metabolite of exemestane in vivo. Previous studies have shown that 17-hydroexemestane is androgenic and bone protective. Due to structure similarities, we hypothesized that, like exemestane, 17-hydroexemestane is an inhibitor of aromatase (CYP19). Our aim was to assess the potency (IC50) of 17-hydroexemestane toward CYP19 inhibition, and to determine the specific CYPs responsible for 17-hydroexemestane metabolism. Using recombinant human CYP19, we investigated the ability of exemestane and 17-hydroexemestane to block the formation of estradiol from testosterone. We found that 17-hydroexemestane potently inhibited aromatase. IC 50 values for the inhibition of CYP19 by exemestane and 17-hydroexemestane were 1.5 μM and 3 μM, respectively. Furthermore, using recombinant human P450s, human liver microsomes, and HPLC analytical techniques, we identified one major metabolite (MIII) of 17-hydroexemestane in the human liver microsomal incubate. In a bank of 15 well-characterized HLMs, MIII formation rate was significantly correlated with the activity of CYP3A (rs= 0.78, p=0.001).In a panel of baculovirus-expressed CYP enzymes, only CYP3A4 and CYP3A5 catalyzed MIII formation at the highest rate. In sum, these in vitro data suggest that 17-hydroexemestane is a potent inhibitor of CYP19 and that CYP3A plays a major role in its metabolism. Whether genetic polymorphisms and drug interactions involving these enzymes may contribute to the disposition and action of 17-hydroexemestane in breast cancer patients remains to be elucidated.