Hydroxysteroid dehydrogenases and pre-receptor regulation of steroid hormone action.

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.