Thiazolidinediones but Not Metformin Directly Inhibit the Steroidogenic Enzymes P450c17 and 3β-Hydroxysteroid Dehydrogenase

• Published in: The Journal of biological chemistry 2001-05, Vol.276 (20), p.16767-16771
• Main Authors: Arlt, Wiebke, Auchus, Richard J., Miller, Walter L.
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M100040200

Androgen biosynthesis requires 3β-hydroxysteroid dehydrogenase type II (3βHSDII) and the 17α-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 3βHSDII, 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 3βHSDII (KI = 25.4 ± 5.1 μm) and both activities of P450c17 (KI for 17α-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 3βHSDII. The thiazolidinediones rosiglitazone and pioglitazone exerted direct but weaker inhibitory effects on both P450c17 and 3βHSDII. 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.