JBC Advanced Glycation Endproducts

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

A more recent version of this article appeared on May 11, 2001
This Article
Right arrow Full Text (Accepted Manuscript)
Right arrow All Versions of this Article:
276/20/16767    most recent
M100040200v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Arlt, W.
Right arrow Articles by Miller, W. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Arlt, W.
Right arrow Articles by Miller, W. L.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Papers In Press, published online ahead of print February 7, 2001
J. Biol. Chem, 10.1074/jbc.M100040200
Submitted on January 2, 2001
Revised on February 6, 2001
Accepted on February 6, 2001

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

Wiebke Arlt, Richard J. Auchus, and Walter L. Miller

Dept. of Pediatrics, University of California (UCSF), San Francisco, CA 94143-0978

Corresponding Author: wlmlab{at}itsa.ucsf.edu

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 while the thiazolidinedione troglitazone inhibited 3beta HSDII (Ki 25.4±5.1 µM) and both activities of P450c17 (Ki values 8.4±0.6 and 5.3±0.7 µM). Troglitazone?s action on P450c17 was competitive, but it was mainly a non-competitive 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, while metformin affects androgen synthesis indirectly, probably by lowering circulating insulin concentrations.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Eur J EndocrinolHome page
M. Jensterle, A. Janez, B. Mlinar, J. Marc, J. Prezelj, and M. Pfeifer
Impact of metformin and rosiglitazone treatment on glucose transporter 4 mRNA expression in women with polycystic ovary syndrome.
Eur. J. Endocrinol., June 1, 2008; 158(6): 793 - 801.
[Abstract] [Full Text] [PDF]

Home page
 The Annals of PharmacotherapyHome page
C. E Murphy and P. T Rodgers
Effects of Thiazolidinediones on Bone Loss and Fracture
Ann. Pharmacother., December 1, 2007; 41(12): 2014 - 2018.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
V. Dhir, H. E. Ivison, N. Krone, C. H. L. Shackleton, A. J. Doherty, P. M. Stewart, and W. Arlt
Differential Inhibition of CYP17A1 and CYP21A2 Activities by the P450 Oxidoreductase Mutant A287P
Mol. Endocrinol., August 1, 2007; 21(8): 1958 - 1968.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
P. Kempna, G. Hofer, P. E. Mullis, and C. E. Fluck
Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2
Mol. Pharmacol., March 1, 2007; 71(3): 787 - 798.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. V. Schwartz, D. E. Sellmeyer, E. Vittinghoff, L. Palermo, B. Lecka-Czernik, K. R. Feingold, E. S. Strotmeyer, H. E. Resnick, L. Carbone, B. A. Beamer, et al.
Thiazolidinedione Use and Bone Loss in Older Diabetic Adults
J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3349 - 3354.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
L. Tosca, P. Solnais, P. Ferre, F. Foufelle, and J. Dupont
Metformin-Induced Stimulation of Adenosine 5' Monophosphate-Activated Protein Kinase (PRKA) Impairs Progesterone Secretion in Rat Granulosa Cells
Biol Reprod, September 1, 2006; 75(3): 342 - 351.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
R. Pasquali and A. Gambineri
Insulin-sensitizing agents in polycystic ovary syndrome.
Eur. J. Endocrinol., June 1, 2006; 154(6): 763 - 775.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
M. Yilmaz, N. Bukan, G. Ayvaz, A. Karakoc, F. Toruner, N. Cakir, and M. Arslan
The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome
Hum. Reprod., December 1, 2005; 20(12): 3333 - 3340.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
E. Diamanti-Kandarakis and C. Piperi
Genetics of polycystic ovary syndrome: searching for the way out of the labyrinth
Hum. Reprod. Update, November 1, 2005; 11(6): 631 - 643.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. J. Betz, I. Shapiro, M. Fassnacht, S. Hahner, M. Reincke, F. Beuschlein, and for the German Austrian Adrenal Network
Peroxisome Proliferator-Activated Receptor-{gamma} Agonists Suppress Adrenocortical Tumor Cell Proliferation and Induce Differentiation
J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 3886 - 3896.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
M.A. Checa, A. Requena, C. Salvador, R. Tur, J. Callejo, J.J. Espinos, F. Fabregues, J. Herrero, and (Reproductive Endocrinology Interest Group of the
Insulin-sensitizing agents: use in pregnancy and as therapy in polycystic ovary syndrome
Hum. Reprod. Update, July 1, 2005; 11(4): 375 - 390.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
V. Sepilian and M. Nagamani
Effects of Rosiglitazone in Obese Women with Polycystic Ovary Syndrome and Severe Insulin Resistance
J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 60 - 65.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
N. Brettenthaler, C. De Geyter, P. R. Huber, and U. Keller
Effect of the Insulin Sensitizer Pioglitazone on Insulin Resistance, Hyperandrogenism, and Ovulatory Dysfunction in Women with Polycystic Ovary Syndrome
J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3835 - 3840.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
M. Guido, D. Romualdi, R. Suriano, M. Giuliani, B. Costantini, R. Apa, and A. Lanzone
Effect of pioglitazone treatment on the adrenal androgen response to corticotrophin in obese patients with polycystic ovary syndrome
Hum. Reprod., March 1, 2004; 19(3): 534 - 539.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
I. Munir, H.-W. Yen, D. H. Geller, D. Torbati, R. M. Bierden, S. R. Weitsman, S. K. Agarwal, and D. A. Magoffin
Insulin Augmentation of 17{alpha}-Hydroxylase Activity Is Mediated by Phosphatidyl Inositol 3-Kinase But Not Extracellular Signal-Regulated Kinase-1/2 in Human Ovarian Theca Cells
Endocrinology, January 1, 2004; 145(1): 175 - 183.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. S. Coffler, K. Patel, M. H. Dahan, R. Y. Yoo, P. J. Malcom, and R. J. Chang
Enhanced Granulosa Cell Responsiveness to Follicle-Stimulating Hormone during Insulin Infusion in Women with Polycystic Ovary Syndrome Treated with Pioglitazone
J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5624 - 5631.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
V. De Leo, A. la Marca, and F. Petraglia
Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome
Endocr. Rev., October 1, 2003; 24(5): 633 - 667.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. V. Pandey, S. H. Mellon, and W. L. Miller
Protein Phosphatase 2A and Phosphoprotein SET Regulate Androgen Production by P450c17
J. Biol. Chem., January 24, 2003; 278(5): 2837 - 2844.
[Abstract] [Full Text] [PDF]

Home page
 Reproductive SciencesHome page
M. F. M. Mitwally, S. F. Witchel, and R. F. Casper
Troglitazone: A Possible Modulator of Ovarian Steroidogenesis
Reproductive Sciences, May 1, 2002; 9(3): 163 - 167.
[Abstract] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
J. D. Veldhuis, G. Zhang, and J. C. Garmey
Troglitazone, an Insulin-Sensitizing Thiazolidinedione, Represses Combined Stimulation by LH and Insulin of de Novo Androgen Biosynthesis by Thecal Cells in Vitro
J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1129 - 1133.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
G. F. Davies, P. J. McFie, R. L. Khandelwal, and W. J. Roesler
Unique Ability of Troglitazone to Up-Regulate Peroxisome Proliferator-Activated Receptor-gamma Expression in Hepatocytes
J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 72 - 77.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
P. D. Schoppee, J. C. Garmey, and J. D. Veldhuis
Putative Activation of the Peroxisome Proliferator-Activated Receptor {gamma} Impairs Androgen and Enhances Progesterone Biosynthesis in Primary Cultures of Porcine Theca Cells
Biol Reprod, January 1, 2002; 66(1): 190 - 198.
[Abstract] [Full Text]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.