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Originally published In Press as doi:10.1074/jbc.M100040200 on February 7, 2001

J. Biol. Chem., Vol. 276, Issue 20, 16767-16771, May 18, 2001
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Thiazolidinediones but Not Metformin Directly Inhibit the Steroidogenic Enzymes P450c17 and 3beta -Hydroxysteroid Dehydrogenase*

Wiebke ArltDagger , Richard J. Auchus§, and Walter L. MillerDagger

From the Dagger  Department of Pediatrics and the Metabolic Research Unit, University of California, San Francisco, California 94143-0978 and the § Department of Medicine, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-8857

Androgen biosynthesis requires 3beta -hydroxysteroid dehydrogenase type II (3beta HSDII) and the 17alpha -hydroxylase and 17,20-lyase activities of cytochrome P450c17. Thiazolidinedione and biguanide drugs, which are used to increase insulin sensitivity in type 2 diabetes, lower serum androgen concentrations in women with polycystic ovary syndrome. However, it is unclear whether this is secondary to increased insulin sensitivity or to direct effects on steroidogenesis. To investigate potential actions of these drugs on P450c17 and 3beta HSDII, we used "humanized yeast" that express these steroidogenic enzymes in microsomal environments. The biguanide metformin had no effect on either enzyme, whereas the thiazolidinedione troglitazone inhibited 3beta HSDII (KI = 25.4 ± 5.1 µM) and both activities of P450c17 (KI for 17alpha -hydroxylase, 8.4 ± 0.6 µM; KI for 17,20-lyase, 5.3 ± 0.7 µM). The action of troglitazone on P450c17 was competitive, but it was mainly a noncompetitive inhibitor of 3beta HSDII. The thiazolidinediones rosiglitazone and pioglitazone exerted direct but weaker inhibitory effects on both P450c17 and 3beta HSDII. These differential effects of the thiazolidinediones do not correlate with their effects on insulin sensitivity, suggesting that distinct regions of the thiazolidinedione molecule mediate these two actions. Thus, thiazolidinediones inhibit two key enzymes in human androgen synthesis contributing to their androgen-lowering effects, whereas metformin affects androgen synthesis indirectly, probably by lowering circulating insulin concentrations.

* This work was supported by National Cooperative Program for Infertility Research Grant U54-HD 34449 (to W. L. M.), National Institutes of Health Grants K08-DK 02387 (to R. J. A.) and R01-DK 37922 (to W. L. M.), and research fellowship Grant Ar 310/2-1 from the Deutsche Forschungsgemeinschaft (to W. A.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pediatrics, Bldg. MR-IV, Rm. 209, University of California, San Francisco, CA 94143-0978. Tel.: 415-476-2598; Fax: 415-476-6286; E-mail: wlmlab@itsa.ucsf.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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