Human Reproduction Update, Vol.9, No.3 pp.193-205, 2003
© European Society of Human Reproduction and Embryology 2003; all rights reserved
Hydroxysteroid dehydrogenases and pre-receptor regulation of steroid hormone action
1 Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
To whom correspondence should be addressed at: Trevor M. Penning, Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia PA 19104-6084, USA. e-mail: penning{at}pharm.med.upenn.edu
Abstract
Steroid target tissues regulate the local level of steroid hormone that can bind and trans-activate nuclear receptors (a process known as intracrine modulation). This pre-receptor regulation can be achieved by hydroxysteroid dehydrogenases (HSDs). For each sex hormone there is a pair of HSD isoforms which act either as reductases or oxidases to convert potent steroid hormones into their cognate inactive metabolites, or vice-versa. In this manner, HSDs can function as molecular switches to regulate steroid hormone action. Because these HSDs show tissue-specific expression, inhibitors of these enzymes are predicted to cause tissue-specific responses to steroid hormones. These inhibitors would represent a new class of therapeutics called ‘selective intracrine modulators’ (SIMs). SIMs are expected to have the same tissue-specific effects as selective steroid receptor modulators but a different mode of action as their effects are enzyme- and not receptor-mediated. HSDs responsible for these interconversions belong to two protein superfamilies: the short-chain dehydrogenases/reductases; and the aldo-keto reductases. Crystal structures exist for HSDs in both families, making rational design of SIMs a reality. Broad-based criteria have been established which must be fulfilled to validate each HSD isoform as a potential SIM target.
Key words: aldo-keto reductase / hydroxysteroid dehydrogenase / short-chain dehydrogenase or reductase/steroid receptor
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Jin, L. Duan, S. H. Lee, H. J. Kloosterboer, I. A. Blair, and T. M. Penning Human Cytosolic Hydroxysteroid Dehydrogenases of the Aldo-ketoreductase Superfamily Catalyze Reduction of Conjugated Steroids: IMPLICATIONS FOR PHASE I AND PHASE II STEROID HORMONE METABOLISM J. Biol. Chem., April 10, 2009; 284(15): 10013 - 10022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Azzarello, K.-M. Fung, and H.-K. Lin Tissue Distribution of Human AKR1C3 and Rat Homolog in the Adult Genitourinary System J. Histochem. Cytochem., September 1, 2008; 56(9): 853 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. McCarthy, R. B. Hochberg, D. C. Labaree, and M. Centrella 3-Ketosteroid Reductase Activity and Expression by Fetal Rat Osteoblasts J. Biol. Chem., November 23, 2007; 282(47): 34003 - 34012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. C. Cooper, Y. Jin, and T. M. Penning Elucidation of a Complete Kinetic Mechanism for a Mammalian Hydroxysteroid Dehydrogenase (HSD) and Identification of All Enzyme Forms on the Reaction Coordinate: THE EXAMPLE OF RAT LIVER 3{alpha}-HSD (AKR1C9) J. Biol. Chem., November 16, 2007; 282(46): 33484 - 33493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. K. Tamashiro, M. M. N. Nguyen, M. M. Ostrander, S. R. Gardner, L. Y. Ma, S. C. Woods, and R. R. Sakai Social stress and recovery: implications for body weight and body composition Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2007; 293(5): R1864 - R1874. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Bryndova, P Klusonova, M Kucka, K Mazancova-Vagnerova, I Miksik, and J Pacha Cloning and expression of chicken 20-hydroxysteroid dehydrogenase J. Mol. Endocrinol., December 1, 2006; 37(3): 453 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Husen, K. Huhtinen, T. Saloniemi, J. Messinger, H. H. Thole, and M. Poutanen Human Hydroxysteroid (17-{beta}) Dehydrogenase 1 Expression Enhances Estrogen Sensitivity of MCF-7 Breast Cancer Cell Xenografts Endocrinology, November 1, 2006; 147(11): 5333 - 5339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L Y Zhou, D S Wang, B Senthilkumaran, M Yoshikuni, Y Shibata, T Kobayashi, C C Sudhakumari, and Y Nagahama Cloning, expression and characterization of three types of 17{beta}-hydroxysteroid dehydrogenases from the Nile tilapia, Oreochromis niloticus J. Mol. Endocrinol., August 1, 2005; 35(1): 103 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Penning AKR1B10: A New Diagnostic Marker of Non-Small Cell Lung Carcinoma in Smokers Clin. Cancer Res., March 1, 2005; 11(5): 1687 - 1690. [Full Text] [PDF]
|
|