17-Hydroexemestane: A Potent Inhibitor of CYP19 (Aromatase) and Substrate of CYP3ALandry KK*, David FA and Zeruesenay D
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- *Corresponding Author:
- Landry Kamdem k
Department of Pharmaceutical Sciences
Harding University College of Pharmacy
915 E. Market Avenue
AR 72149, Box 12230
E-mail: [email protected]
Received date: August 23, 2014; Accepted date: September 22, 2014; Published date: September 28, 2014
Citation: Landry KK, David FA, Zeruesenay D (2014) 17-Hydroexemestane: A Potent Inhibitor of CYP19 (Aromatase) and Substrate of CYP3A. J Drug Metab Toxicol 5:171. doi: 10.4172/2157-7609.1000171
Copyright: © 2014 Landry KK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.