Donald Poirier Pages 453 - 477 ( 25 )
The 17β-hydroxysteroid dehydrogenases (17β-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 17β-hydroxysteroids using NAD(P)H or NAD(P)+ as cofactor. The enzyme activities associated with the different 17β-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 17β-HSD were reported, indicating that a fine regulation is carried out. More importantly, each type of 17β-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 17β-HSD family. From a therapeutic point of view, this means that selectivity of drug action could be achieved by targeting a particular 17β-HSD isozyme. Consequently, each study that leads to better knowledge of the inhibition of 17β-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 17β-HSD family constitutes an interesting target for controlling the concentration of estrogens and androgens. Thus, inhibitors of 17β-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 17β-HSD inhibitors although this family of steroidogenic enzymes includes interesting therapeutic targets for the control of several diseases. Furthermore, inhibitors of 17β-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 17β-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.
enzyme,Inhibitor,hydroxysteroid dehydrogenase,steroid,estrogen,androgen,hormone
Medicinal ChemistryDivision, Oncology and Molecular Endocrinology Research Center,Centre Hospitalier Universitaire de Quebec (CHUQ), Pavillon CHUL,2705 Laurier Boulevard, Sainte-Foy, Quebec, G1V 4G2, Canada