Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3β-hydroxysteroid dehydrogenase
File(s)
Published version
Author(s)
Arlt, W
Auchus, RJ
Miller, WL
Type
Journal Article
Abstract
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.
Date Issued
2001-05-18
Date Acceptance
2001-05-01
Citation
Journal of Biological Chemistry, 2001, 276 (20), pp.16767-16771
ISSN
0021-9258
Publisher
Elsevier
Start Page
16767
End Page
16771
Journal / Book Title
Journal of Biological Chemistry
Volume
276
Issue
20
Copyright Statement
© 2001 by The American Society for Biochemistry and Molecular Biology, Inc. This is an Open Access article under the CC BY license.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/11278997
PII: S0021-9258(19)31844-7
Subjects
17,20-LYASE ACTIVITY
17-ALPHA-HYDROXYLASE
ACTIVATED RECEPTOR-GAMMA
Biochemistry & Molecular Biology
CYTOCHROME B(5)
DEPENDENT DIABETES-MELLITUS
INSULIN-RESISTANCE
Life Sciences & Biomedicine
OBESE WOMEN
POLYCYSTIC-OVARY-SYNDROME
RESPIRATORY-CHAIN
Science & Technology
TROGLITAZONE
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2001-05-18