Analysis and characteristics of multiple types of human 17β-hydroxysteroid dehydrogenase

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Abstract

Androgens and estrogens are not only synthesized in the gonads but also in peripheral target tissues. Accordingly, recent molecular cloning has allowed us to identify multiple types of 17β-hydroxysteroid dehydrogenases (17β-HSD), the key and exclusive enzymes involved in the formation and inactivation of sex steroids. However, only one form, namely, type 3 17β-HSD, is responsible for pseudohermaphroditism in deficient boys. To date, seven human 17β-HSDs have been isolated and characterized. Although they catalyze substrates having a similar structure, 17β-HSDs have very low homology. In intact cells in culture, these enzymes catalyze the reaction in a unidirectional way — types 1, 3, 5 and 7 catalyze the reductive reaction, while types 2, 4 and 8 catalyze the oxidative reaction. It is noteworthy that rat type 6 17β-HSD also catalyzes the reaction in the oxidative direction. In this report, we analyze the different characteristics of the multiple types of human 17β-HSD.

Introduction

The 17β-hydroxysteroid dehydrogenases (17β-HSDs) are enzymes involved in the formation of active sex steroids, namely testosterone (T), estradiol (E2), 5-androstenediol (5-diol) and dihydrotestosterone (DHT). They catalyze the last and key step in the formation of all estrogens and androgens since sex steroids require the presence of a hydroxy group at position 17β on the steroid nucleus. The most widely known is the testicular enzyme, which catalyzes the transformation of 4-androstenedione (4-dione) into testosterone (T) [1]. Its impairment in the male embryo leads to male pseudohermaphroditism characterized by the absence of the male internal reproductive structures (epididymis, seminal vesicles and vas deferens) that are normally formed from Wolffian ducts under the control of T. Because of the existence of multiple diseases due to the deficiency of gonadal sex steroid production and the belief that steroids were freely distributed through blood circulation, it was generally believed until recently that sex steroids were produced exclusively by the gonads. However, this belief was proven wrong by studies performed in men who had their testicles removed or their testicular androgen secretion totally blocked by a treatment with an agonist of luteinizing hormone-releasing hormone (LHRH, see [2], [3] for reviews). It was found that, while their testosterone blood level was reduced by 90–95% following castration, their intraprostatic concentration of DHT was decreased by only 50%, thus, suggesting an intraprostatic biosynthesis of androgens. The development of secondary sexual characters in young boys deficient in the type 2 3β-HSD is a natural proof of the conversion of adrenal precursors dehydroepiandrosterone (DHEA) into active sex steroids in target tissues. In recent years, the existence of a local biosynthesis of sex steroids in peripheral tissues was further confirmed by the cloning of multiple types of steroidogenic enzymes, namely type 1 and 2 3β-HSD [4], [5], [6], [7], [8], type 1 [9], type 2 [10], [11], type 3 [12], type 5 [13] and type 7 [14] 17β-HSD as well as type 1 [15], [16] and type 2 [17], [18] 5α-reductases. The expression of these enzymes is tissue-specific, some being expressed only in peripheral tissues. Furthermore, it has been clearly demonstrated that certain congenital diseases are due to a deficiency in a single form of an enzyme. For example, a deficiency in type 2 3β-HSD [19], [20] is responsible for congenital adrenal hyperplasia; a deficiency of type 2 5α-reductase [21] and/or type 3 17β-HSD [12] causes male pseudohermaphroditism. This supports strongly the finding that peripheral tissues possess their own steroidogenic enzymes responsible for an independent biosynthesis of androgens and estrogens from DHEA and/or its sulfate (DHEAS). These precursors are secreted by the adrenals of humans and a few other primates but not in animals of the lower species.

Section snippets

Multiple 17β-HSDs and intracrinology

The formation of estradiol (E2) from estrone (E1), of T from 4-dione, of 5-androstene-3β,17β-diol (5-diol) from DHEA, of DHT from 5α-androstane-3,17-dione (A-dione) and their respective reverse reactions are catalyzed by 17β-HSDs (Fig. 1), which are distributed widely in human tissues. In fact, 17β-HSD activity is not only present in classical steroidogenic tissues, such as the human placenta [9], [22], ovary [23], and testis [1], [12], but also in a large series of peripheral intracrine

Unidirectional activity of 17β-HSDs

By analogy to almost all other dehydrogenases, 17β-hydroxysteroid dehydrogenases were until recently considered to be reversible enzymes that catalyze the interconversion of substrates and products, mainly because they were first characterized using tissue homogenates or subfractions or purified proteins with added oxidized (NAD+/NADP+) or reduced (NADH/NADPH) cofactors. These exogenous cofactors drive the reaction in the oxidative or reductive direction depending upon their oxidized or reduced

Local control of estrogen and androgen formation and inactivation by 17β-HSDs

It is well recognized that sex steroids play a predominant role in the regulation of cell growth and differentiation of the normal prostate and mammary gland, as well as in hormone-sensitive prostate and breast carcinomas. It is generally accepted that, while estrogens stimulate the proliferation of hormone-sensitive breast cancer cells [67], [68], [69], [70], androgens exert an antiproliferative action on these cells [67], [71], [72], [73].

In the case of hormones provided to the cells from

Differential characteristics of 17β-HSDs of human and laboratory animals

The characteristics of 17β-HSDs and other steroidogenic enzymes of rodents are different from those of their human counterparts. Indeed, while human type 1 17β-HSD is selective for the transformation of E1 into E2 [45], the mouse enzyme also transforms C19-steroids [76]. Human type 5 17β-HSD is highly labile upon homogenization of the cells. In contrast, the mouse enzyme is stable and is not altered by homogenization [13]. Most importantly, they also show different substrate specificity

Divergence of different types of 17β-HSD on the evolutionary scale

Within a given species, the different types of 17β-HSDs share very low homology (approximately 20%) but catalyze closely the related activities, they catalyze the oxidation and/or reduction of the oxygen atom located at position 17 of the steroid nucleus. However, orthologs of each type can be formed in other species at the normal percentage of homology for orthologs. In contrast, different types of human 3β-HSD and aldo–keto reductases are highly homologous. Their percentage of identity could

Acknowledgements

This work was supported by grants from Medical Research Council of Canada and Endorecherche, Inc.

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