Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3 beta-hydroxysteroid dehydrogenase

Androgen biosynthesis requires 3 beta -hydroxysteroid dehydrogenase type II (3 beta HSDII) and the 17 alpha -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 co ncentrations in women with polycystic ovary syndrome. However, it is unclea r whether this is secondary to increased insulin sensitivity or to direct e ffects on steroidogenesis, To investigate potential actions of these drugs on P450c17 and 3 beta HSDII, we used "humanized yeast" that express these s teroidogenic enzymes in microsomal environments. The biguanide metformin ha d no effect on either enzyme, whereas the thiazolidinedione troglitazone in hibited 3 beta HSDII (K-I = 25.4 +/- 5.1 muM) and both activities of P450c1 7 (K-I for 17 alpha -hydroxylase, 8.4 +/- 0.6 muM; K-I for 17,20-lyase, 5.3 +/- 0.7 mum) The action of troglitazone on P450c17 was competitive, but it was mainly a noncompetitive inhibitor of 3 beta HSDII, The thiazolidinedio nes rosiglitazone and pioglitazone exerted direct but weaker inhibitory eff ects on both P450c17 and 3 beta HSDII, These differential effects of the th iazolidinediones do not correlate with their effects on insulin sensitivity , suggesting that distinct regions of the thiazolidinedione molecule mediat e these two actions. Thus, thiazolidinediones inhibit two key enzymes in hu man androgen synthesis contributing to their androgen-lowering effects, whe reas metformin affects androgen synthesis indirectly, probably by lowering circulating insulin concentrations.