**1. Introduction**

114 Dehydrogenases

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Hydroxysteroid dehydrogenases (HSDs) belong to the NADPH/NAD+-dependent oxidoreductases, which interconvert ketones and the corresponding secondary alcohols. As their names imply, they catalyze the oxidoreduction in different positions of steroidal substrates (3α-, 3β-, 11β-, 17β-, 20α- and 20β-position). The steroid-converting HSDs play central roles in the biosynthesis and inactivation of steroid hormones, but some of them are also involved in the metabolism of diverse non-steroidal compounds [1]. The HSDs are integral parts of systemic (endocrine) and local (intracrine) mechanisms. In target tissues they convert inactive steroid hormones to their corresponding active forms and viceversa, thus modulating the transactivation of steroid hormone receptors or other elements of the non-genomic signal transduction pathways. Therefore, HSDs act as molecular switches allowing pre-receptor modulation of steroid hormone action [2].

It is also well recognized that human and certain other primates are unique among animal species in having adrenals that secrete large amounts of inactive steroid precursors including dehydroepiandrosterone (DHEA). These steroids do not bind to the androgen receptor but exert either estrogenic or androgenic action after their conversion into active estrogens and/or androgens in target tissues [3]. Imbalanced action of sex steroid hormones, i.e. androgens and estrogens, is involved in the pathogenesis of various severe diseases in human. Hormone-dependent cancers are commonly lethal both in women and in men, with breast cancer being the most prevalent cancer in women and prostate cancer in men in several Western countries [4]. In addition, there are various other common hormonedependent diseases, such as polycystic ovary syndrome (PCOS) and endometriosis, having poorly understood aetiology and lacking efficient pharmacological treatment [5, 6]. However, changes in circulating hormone concentrations do not explain all pathophysiological processes occured in hormone-dependent tissues. A more inclusive explanation is provided by paracrine and intracrine action of sex steroids, namely the

© 2012 Atanassova and Koeva, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

regulation of intratissue hormone concentrations by expression of steroidogenic enzymes. The modulation of local sex steroid production using pharmaceutical compounds is also a valuable treatment option for developing of novel therapies against hormonal diseases [7]. In the view of successful practice of inhibiting of non-HSD enzymes (aromatase and 5αreductase) [8, 9], recent attempt are made for development of HSD inhibitors as therapeutic strategy. Several of HSD enzymes are also considered as promising drug targets and inhibitors, for example most of the isoforms of 17β-HSD enzyme [10].

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 117

xydroxylation (introduction of hydroxyl group –OH into organic compound) and cleavage of the steroid substrate utilizing molecular oxygen and nicotinamide adenine dinucleotide phosphate (NADPH, reduced) as the source of reductive potential. Several enzymes are included: cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc, *CYP11A1)*, cytochrome P450 17α-hydroxylase (P450c17, 17α-hydroxylase, 17-20 lyase, *CYP17A1*), P450 aromatase (aromatase, *CYP19A1*), 21α-hydroxylase (*CYP21A*), 11β-hydroxylase (*CYP11B1)* and aldosterone synthase (*CYP11B2*). The second class of steroidogenic enzymes, HSD enzymes called alcohol oxydoreductases catalyze the dehydrogenation of hydroxysteroids. Acting as oxydoreductases, HSD enzymes require nicotinamide adenine dinucleotide (NAD, oxidized) and/or NADPH as electron acceptor/donor. HSD enzymes include: 3βhydroxysteroid dehydrogenase (3β-HSD),11β-hydroxysteroid dehydrogenase (11β-HSD) and 17β-hydroxysteroid dehydrogenase (17β-HSD). While each P450 enzyme is the product of a single gene, the HSD enzymes have several isoforms that are products of distinct genes

In all species, the first and rate-limiting step in steroidogenesis, in particular androgen biosynthesis, is conversion of the C27 cholesterol to the C21 steroid, pregnenolone (Figure 1). This reaction is catalyzed by cytochrome P450scc enzyme located in the inner mitochondrial membrane. Pregnenolone diffuses across the mitochondrial membrane and it is further metabolized by enzymes associated with the smooth endoplasmic reticulum. These enzymes are: 1) cytochrome P450c17, which catalyzes the conversion of the C21 steroids pregnenolone or progesterone to the C19 steroids dehydroepiandrosterone or androstenedione, respectively; 2) 3β-HSD (∆5-∆4 isomerase), which catalyzes the conversion of the ∆5 hydroxysteroids - pregnenolone or dehydroepiandrosterone to the ∆4 ketosteroids - progesterone or androstenedione, respectively; 3) 17β-HSD (17-ketosteroid reductase),

Corticosteroids (mineralocorticoids and glucocorticoids, C-21 cabons) derive from progestagens (progesterone and 17α-OH progesterone) after hydroxylation of carbon-21 by the enzyme 21α-hydroxylase. So, aldosterone and corticosterone share the first part of their biosynthetic pathway. The last part is mediated either by aldosterone synthase (for aldosterone) or by 11β-hydroxylase (for corticosterone). These enzymes are nearly identical (they share 11β-hydroxylation and 18-hydroxylation functions). Aldosterone synthase is also able to perform 18-oxidation. 11β-hydroxysteroid dehydrogenase (11β-HSD) catalyzes the conversion of active cortisol to inert 11 keto-products (cortisone), or vice versa, thus

The steroidogenic pathays/steroid output are controlled by complex regulatory mechanisms that involved wide range of factors like pituitary trophic hormones, growth factors, cytokines and steroids. The major factors, expressed since early fetal life, are steroidogenic acute regulatory protein (StAR) and Steroidogenic Factor-1 (SF-1). StAR actively transports cholesterol from the outer to the inner mitochondrial membrane and allows *CYP11A* (located in the inner membrane) access to cholesterol [17]. Cell specific expression of StAR and P450 enzymes are regulated by Steroidogenic Factor-1 (SF-1), which binds to promoter region of StAR gene and of all CYP genes, activating their expression [18, 19]. The most compelling

[15]. There are four types, classified by the number of the carbon acted upon.

which catalyzes the final step in the biosynthesis of testosterone [16].

regulating the access of glucocorticoids to the steroid receptors.

In this review, we summarise the data from the literatute and our own data on the main HSDs (11β-HSD, 3β-HSD 17β-HSD) focusing our attention on the localization/tissue distribution and regulation of the enzyme isoforms and their role in normal and pathological processes as revealed by experimental models and clinical observations. The review would provide better understanding on multifunctionality of HSDs and their relevance to the clinic and that would be helpful for scientists and clinicians, working in a new challenging area of development of HSD-inhibitors as new drugs for hormone-related deceases.
