Vihko and Isomaa: 17!-hydroxysteroid dehydrogenases and breast cancer capable of performing de novo steroid synthesis but contain the enzymes needed for the formation of active androgens and estrogens form adrenal-derived C19 steroids, such as dehydroepiandrosterone, its sulphate and androstenedione, which are abundantly secreted into the circulation in humans (Labrie et al, 1997). These steroids serve as substrates in peripheral tissues and locally produced active steroids exert their action in the intracrine manner on the same cell in which they are synthesized without diffusion into the circulation and, therefore, effectively regulate sex steroid influence at the prereceptor level in the target cells. The enzymes modulating sex steroid metabolism and, consequently, the concentration of active steroids in peripheral tissues include steroid sulphatases, 3!-hydroxysteroid dehydrogenases, 3"-hydroxysteroid dehydrogenases, aromatase, 17!-hydroxysteroid dehydrogenases and 5"reductases. We have focused our studies on 17!-hydroxysteroid dehydrogenases (17HSDs), which regulate the biological activity of sex steroid hormones by catalyzing the interconversions between highly active steroid hormones, e.g. estradiol and testosterone and corresponding less active hormones, estrone and androstenedione (Figure 1). Up till now, at least nine different 17HSD isoenzymes, namely the types 1-5, 7-8 and 10-11 (Peltoketo et al, 2003; Mindnich et al, 2004), have been characterized in humans. In intact cells, the types 1, 3, 5 and 7 mainly catalyze reductive reactions, whereas the other types are considered as oxidative enzymes. The presence of a series of 17HSD enzymes with cell-specific expression patterns and differential substrate specificities point to the important role of 17HSDs in intracrine steroid formation.
Human 17HSD type 1 catalyzes the reduction of estrone to estradiol (Puranen et al, 1997), preferring the phosphorylated form of nicotinamide-adenine dinucleotide, NADPH, as a cofactor. In cultured cells, the human type 1 enzyme is also capable of reducing androstenedione and 5"-androstanedione to some extent, but it clearly gives preference to phenolic substrates over androgens. 17HSD type 1 is essential for estradiol production and it is most abundantly expressed in the granulosa cells of the ovary (Ghersevich et al, 1994; Sawetawan et al, 1994) and the syncytiotrophoblasts of the placenta (Fournet-Dulguerov et al, 1987; M채entausta et al, 1990), which secrete estradiol into the circulation. In addition, the type 1 enzyme contributes to the estrogen response by converting estrone to estradiol locally in certain targets of estrogen action, such as normal and malignant breast tissue (Poutanen et al, 1995; Miettinen et al, 1996a). 17HSD type 2 is involved in the inactivation of estradiol, testosterone and dihydrotestosterone (DHT) and the activation of progesterone. 17HSD type 2 is expressed in a wide variety of tissues, such as breast, uterus, prostate, placenta, liver, intestine and kidney (Peltoketo et al, 1999; 2003). Typically, the type 2 enzyme is expressed in epithelial cells, such as the surface epithelial cells of the gastrointestinal and urinary tracts (Mustonen et al, 1998a; Oduwole et al, 2003). The type 2 enzyme may restrict the access of active sex steroids into the circulation and it may protect the target tissues of hormonal action against excessive sex hormone influence by catalyzing the conversion of androgens and estrogens into less active forms. In the placenta, the type 2 enzyme may limit the access of fetal androgens into the maternal tissue and the access of maternal estrogen into the fetus, acting as a barrier between the fetus and the mother (Mustonen et al, 1998b, Li et al, 2005).
II. Enzymatic characteristics of human 17HSD type 1, type 2, type 5 and type 7
Figure 1. The key reactions in the metabolism of estrogens and androgens. A-dione = androstenedione; 17HSD1, 2 etc. refer to different 17HSD-enzymes; P450arom = P450 aromatase enzyme.
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