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Inhibitors of 17 beta-hydroxysteroid dehydrogenases.

Abstract
The 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) play an important role in the regulation of steroid hormones, such as estrogens and androgens, by catalysing the reduction of 17-ketosteroids or the oxidation of 17beta-hydroxysteroids using NAD(P)H or NAD(P)(+) as cofactor. The enzyme activities associated with the different 17beta-HSD isoforms are widespread in human tissues, not only in classic steroidogenic tissues, such as the testis, ovary, and placenta, but also in a large series of peripheral intracrine tissues. In the nineties, several new types of 17beta-HSD were reported, indicating that a fine regulation is carried out. More importantly, each type of 17beta-HSD has a selective substrate affinity, directional (reductive or oxidative) activity in intact cells, and a particular tissue distribution. These findings are important for understanding the mode of action of the 17beta-HSD family. From a therapeutic point of view, this means that selectivity of drug action could be achieved by targeting a particular 17beta-HSD isozyme. Consequently, each study that leads to better knowledge of the inhibition of 17beta-HSDs deserves attention from scientists working in this and related fields. Being involved in the last step of the biosynthesis of sex steroids from cholesterol, the 17beta-HSD family constitutes an interesting target for controlling the concentration of estrogens and androgens. Thus, inhibitors of 17beta-HSDs are useful tools to elucidate the role of these enzymes in particular biological systems or for a therapeutic purpose, especially to block the formation of active hydroxysteroids that stimulate estrogeno-sensitive pathologies (breast, ovarian, and endometrium cancers) and androgeno-sensitive pathologies (prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc). Few review articles have however focussed on 17beta-HSD inhibitors although this family of steroidogenic enzymes includes interesting therapeutic targets for the control of several diseases. Furthermore, inhibitors of 17beta-HSDs constitute a growing field in biomedical research and there is a need for an exhaustive review on this topic. In addition to giving an up-to-date description of inhibitors of all 17beta-HSD isoforms (types 1-8), the present review will also address, when possible, the isoform selectivity and residual estrogenic or androgenic activity often associated with steroidal inhibitors.
AuthorsDonald Poirier
JournalCurrent medicinal chemistry (Curr Med Chem) Vol. 10 Issue 6 Pg. 453-77 (Mar 2003) ISSN: 0929-8673 [Print] United Arab Emirates
PMID12570693 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
Chemical References
  • Androgens
  • Enzyme Inhibitors
  • Estrogens
  • Isoenzymes
  • Receptors, Androgen
  • Receptors, Estrogen
  • NADP
  • 17-Hydroxysteroid Dehydrogenases
  • 3 (or 17)-beta-hydroxysteroid dehydrogenase
Topics
  • 17-Hydroxysteroid Dehydrogenases (antagonists & inhibitors)
  • Androgens (metabolism)
  • Animals
  • Enzyme Inhibitors (pharmacology)
  • Estrogens (metabolism)
  • Evolution, Molecular
  • Female
  • Humans
  • Isoenzymes (genetics, metabolism)
  • Male
  • NADP (pharmacology)
  • Receptors, Androgen (genetics)
  • Receptors, Estrogen (genetics)

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