Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.3 (HSD)
3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leydig cells are a target for their own steroid product, testosterone, and thus could be subject to short-loop feedback regulation by androgens. The authors previously reported that 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta HSD) activity was higher in freshly isolated Leydig cells from C57BL/6J than those from C3H/HeJ inbred mice. To determine whether this strain-related difference in 3 beta HSD activity could be mediated by differential sensitivity to feedback effects of testosterone, Leydig cells from the two strains were cultured in the presence or absence of testosterone, the synthetic androgen receptor agonist, mibolerone, or the nonaromatizable androgen, dihydrotestosterone. After 7 days of treatment, all three androgens significantly decreased 3 beta HSD activity in Leydig cells from C57BL/6J, but not from C3H/HeJ mice. When Leydig cells were cultured with hydroxyflutamide, an androgen receptor antagonist, the effect of testosterone was negated. To determine whether the strain-related difference in sensitivity to testosterone was mediated by a difference in the androgen receptor protein, Leydig cells from reciprocal F1 hybrid lines of mice were cultured in the presence or absence of testosterone. Testosterone treatment inhibited 3 beta HSD activity in both F1 lines to the same extent as observed for Leydig cells from C57BL/6J mice. Thus, there is a strain-related difference in the response to testosterone, but it cannot account for the strain-related difference in Leydig cell 3 beta HSD activity because the high 3 beta HSD strain (C57BL/6J) is the sensitive strain. Although the effect on C57BL/6J Leydig cells is androgen receptor-mediated, the dominant effect of testosterone on both F1 lines rules out a difference in the androgen receptor protein per se. However, the data are consistent with the difference being in a trans-acting factor distal to the androgen receptor.
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PMID:Evidence that testosterone regulates Leydig cell 3 beta-hydroxysteroid dehydrogenase-isomerase activity by a trans-acting factor distal to the androgen receptor. 155 11

Leydig cell progenitors contain significant concentrations of androgen receptors. When the metabolism of DHT to 3 alpha-DIOL is blocked, DHT stimulates testosterone production by Leydig cell progenitors, most probably via an androgen receptor dependent mechanism. Rapid metabolism by 3 alpha-HSD may limit the potency of exogenous DHT to stimulate differentiation of Leydig cell progenitors in vitro. Insulin-like growth factor-I enhances androgen production by purified immature Leydig cells. The elevated sensitivity of immature Leydig cells versus adult Leydig cells to IGF-I stimulation indicates that this peptide hormone has a role in their differentiation during puberty.
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PMID:Hormonal control of Leydig cell differentiation. 178 69

The ovarian enzyme 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) converts dihydrotestosterone (DHT) to 5 alpha-androstan-3 alpha,17 beta-diol (3 alpha-diol), a reduced androgen that does not bind to the granulosa cell androgen receptor. To determine the relative contribution of the granulosa cells to total ovarian 3 alpha-HSD activity, adult rats treated with either medroxyprogesterone acetate (MPA) or vehicle underwent ovarian microdissection. 3 alpha-Hydroxysteroid dehydrogenase is primarily located in excised follicles and corpora lutea, and is inhibited in the follicles but not corpora lutea by MPA (P less than 0.05). Elimination of healthy granulosa cells while maintaining healthy theca cells by irradiation of the exteriorized ovaries with 6000 rads resulted in a marked reduction in 3 alpha-HSD to 19% of control levels on a per-organ basis (P less than 0.01). The granulosa cell is the major ovarian site for 3 alpha-hydroxylation of ring A-reduced C19 steroids in the adult rat.
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PMID:Evidence for a granulosa cell site of dihydrostestosterone metabolism in the adult rat ovary. 293 97

Dicyclohexane derivatives, which inhibit the binding of testosterone and dihydrotestosterone (DHT) to the androgen-binding protein (ABP) of rat epididymis without interfering with their binding to the androgen receptor, show a similar selectivity in their effects on androgen metabolism. Their ability to inhibit the aromatization of testosterone has been reported previously. This paper demonstrates that they are potent inhibitors of 3 alpha(beta)-hydroxysteroid:NAD(P)+ oxidoreductase activity (3-HSD) in the particulate fraction from rat prostate gland; the values of Ki for their inhibition of this enzyme are similar to that of the Km for DHT as substrate. The dicyclohexane derivatives are markedly less effective against the cytosolic NADPH-dependent 3-HSD, and they do not appear to inhibit testosterone 5 alpha-reductase activity. These characteristics are likely to complicate the proposed use of the dicyclohexane derivatives as probes for the role of ABP in vivo. However, they may be of interest in the study of structure-activity relationships in androgen-metabolizing enzymes, particularly in the examination of the different forms of 3-HSD.
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PMID:Effects of dicyclohexane derivatives on androgen metabolism in the rat prostate. 386 28

In gonadectomized rats of either sex s.c. administration of 5 alpha-dihydrotestosterone (DHT) reversed, in a dose dependent manner, effects brought about by gonadectomy: it decreased pituitary wet weight and serum levels of LH and FSH and suppressed microsomal enzyme activities involved in testosterone and progesterone metabolism in the pituitary gland, NADPH-linked 5 alpha-reductase and NADH-linked 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSDH). Concomitantly administered nonsteroidal antiandrogen, flutamide (5 mg/day), antagonized some of the suppressive effects induced by a 14-day treatment of gonadectomized rats with high dose (1 mg/day) of DHT. It completely blocked DHT action on pituitary 5 alpha-reductase activity in the female rat and, in the male, inhibition was found to be 30-35%. In male, but not female rats, it completely blocked DHT suppression of serum FSH level whereas it slightly, but significantly inhibited DHT suppression of serum LH in rats of either sex. However, flutamide did not prevent DHT suppression of pituitary wet weight or NADH-linked 3 alpha-HSDH activity. Concomitantly administered progestational antiandrogen, cyproterone acetate (5 mg/day), inhibited DHT-induced weight increase of seminal vesicles by 50-55% and completely blocked the weight decrease of pituitary gland but did not antagonize DHT suppression of serum gonadotropins or pituitary enzyme activities. The results obtained with flutamide suggest that DHT-induced suppression of pituitary NADPH-linked 5 alpha-reductase, but not NADH-linked 3 alpha-HSDH activity, might involve an androgen receptor mechanism.
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PMID:The action of 5 alpha-dihydrotestosterone and antiandrogens on the activities of 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase in the pituitary gland of gonadectomized rats. 680 44

In order to investigate the mode of action of testosterone (T) on human hair follicles we studied the metabolism of T and localization of androgen receptors in outer root sheath cells (ORSC) and dermal papilla cells (DPC) from different body sites. T was principally metabolized to androstenedione (delta 4) even in beard ORSC as well as epidermal keratinocytes (EK), and the ratio of apparent 5 alpha-reductase (5 alpha-R) to 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) did not differ between these two kinds of cells. The 5 alpha-R activity in beard DPC was 3 times as high as that in occipital scalp and axillary DPC. The 5 alpha-R of beard DPC exhibited a narrow optimum pH of 5.5, which is characteristic of type 2 enzyme present in androgen target cells. In contrast, 5 alpha-R of DPC from axillary and occipital scalp hair showed a broad optimum pH range between 6.5-9.0 corresponding to type 1 5 alpha-R. Androgen receptors were detected in the DPC of beard and axillary hair follicles, but not in those of occipital scalp hair follicles using immunohistochemical staining with polyclonal anti-androgen receptor antibody. Epithelial cells of the hair bulb were not stained by the antibody. Androgen receptors were also detected in the nuclei of cultured beard and axillary DPC, but the DPC from occipital scalp hair follicles showed little staining with the antibody. We also examined the effects of T on the DNA synthesis and proliferation of cultured ORSC and DPC. T did not have a proliferative effect on either type of cell when cultured alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of action of androgen in hair follicles. 799 80

The estrogen-sensitive human breast cancer cell line ZR-75-1 was used to study the regulation of 17 beta-hydroxysteroid dehydrogenase (17 beta HSD), the enzyme responsible for the interconversion of estrone (E1) and estradiol (E2). We, thus, investigated the effects of a 6-day exposure to various steroids or growth factors on the reductive (E1-->E2) and oxidative (E2-->E1) 17 beta HSD activities in ZR-75-1 cells as measured during a subsequent 16-h incubation with [3H]E1 or [3H]E2. The reductive 17 beta HSD activity was approximately 3-fold higher than the corresponding oxidative (E2-->E1) activity in control cells, thus favoring the predominance of E2 within the cell. Exposure to dihydrotestosterone (DHT) increased by 1.4-fold the reductive 17 beta HSD activity, with the stimulatory effect exerted at an EC50 value of 0.09 nM DHT, while the oxidative pathway was increased by 4.15-fold at an EC50 value of 0.17 nM. Incubation with medroxyprogesterone acetate, on the other hand, enhanced reductive 17 beta HSD activity by 1.87-fold, while the same treatment increased oxidative 17 beta HSD activity by 2.85-fold; the effects were exerted at EC50 values of 0.4 and 5 nM, respectively. The stimulatory effect of both steroids on 17 beta HSD activity was almost completely reversed by simultaneous exposure to the pure antiandrogen hydroxyflutamide (3 microM), thus supporting an action exerted through the androgen receptor. On the other hand, the synthetic estrogen ethynyl estradiol (EE2) inhibited the reductive and oxidative 17 beta HSD activities by 40% and 33%, respectively, whereas dexamethasone (300 nM) increased by 2.5- and 1.9-fold the reductive and oxidative 17 beta HSD activities, respectively. The present data showing that DHT and the androgenic compound medroxyprogesterone acetate favor the degradation of E2 into E1 suggest that the potent antiproliferative activity of these two compounds in E2-stimulated ZR-75-1 human breast cancer cells could be at least partially exerted through changes in 17 beta HSD activity.
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PMID:Androgen receptor-mediated stimulation of 17 beta-hydroxysteroid dehydrogenase activity by dihydrotestosterone and medroxyprogesterone acetate in ZR-75-1 human breast cancer cells. 838 Mar 73

The Leydig cell from the immature pig provides a good model for studying testicular steroidogenesis. Regulation of the enzymes involved, which has been well studied in rodents, has not been characterized in the pig. The objectives of this study were to examine the regulation of three steroidogenic enzymes in pig Leydig cells by LH/hCG and testosterone. The mRNA for P450 side-chain cleavage and P450(17) alpha-hydroxylase/C17-20-lyase, although constitutively expressed, decreased over time in culture, while that for 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) remained relatively constant. The mRNA for all three enzymes was increased in a dose- and time-dependent manner by treatment with hCG. Run-on experiments demonstrated that the main effect of the hormone was at the level of transcription. Treatment with hydroxyflutamide, either alone or in combination with hCG, had no effect on the mRNA for these enzymes. Treatment with hCG plus aminoglutethimide, an inhibitor of steroidogenesis, had no effect on the mRNA for the two P450 enzymes, but resulted in an increase in mRNA for 3 beta HSD when compared to treatment with hCG alone. However, exogenous testosterone could not block the effect of aminoglutethimide. Therefore, the steroidal regulation of 3 beta HSD in pig Leydig cells may act through a mechanism separate from the androgen receptor. While aspects of the regulation of these enzymes are similar to those seen in rodents, some significant differences exist. Our results support the concept that regulation of steroidogenic enzymes in Leydig cells is species-specific.
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PMID:Regulation by gonadotropins of the messenger ribonucleic acid for P450 side-chain cleavage, P450(17) alpha-hydroxylase/C17,20-lyase, and 3 beta-hydroxysteroid dehydrogenase in cultured pig Leydig cells. 882 39

Mammalian 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSDs) regulate steroid hormone levels. For example, hepatic 3 alpha-HSDs inactivate circulating androgens, progestins, and glucocorticoids. In target tissues they regulate access of steroid hormones to steroid hormone receptors. For example, in the prostate 3 alpha-HSD acts as a molecular switch and controls the amount of 5 alpha-dihydrotestosterone that can bind to the androgen receptor, while in the brain 3 alpha-HSD can regulate the amount of tetrahydrosteroids that can alter GABAa receptor function. Molecular cloning indicates that these mammalian 3 alpha-HSDs belong to the aldo-keto reductase superfamily and that they are highly homologous proteins. Using the three-dimensional structure of rat liver 3 alpha-HSD as a template for site-directed mutagenesis, details regarding structure function relationships, including catalysis and cofactor and steroid hormone recognition have been elucidated. These details may be relevant to all mammalian 3 alpha-HSDs.
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PMID:Mammalian 3 alpha-hydroxysteroid dehydrogenases. 888 17

Among the new antral follicles that develop after ovulation in pigs, the incidence of atresia, based on granulosa cell apoptosis, increases between Days 5 and 7 of the estrous cycle. The purpose of this study was to determine how follicular growth and atresia affected the expression of some key enzymes regulating follicular steroidogenesis and androgen receptor on Days 3, 5, and 7 after the onset of estrus. Ovaries were frozen in liquid propane for subsequent sectioning and immunohistochemical analysis. Ninety-six follicles were classified according to size as small (< 3 mm), medium (3-5 mm), or large (> 5 mm). Follicles in the active stages of the cell cycle were identified by the presence of the cell proliferation-associated nuclear antigen Ki-67 in granulosa cells. Follicles with apoptotic cells were identified by in situ 3'-end labeling of DNA. Staining intensity of antigens on sections was assigned a numeric value (0-3). Follicles assigned a value > 1 for 3'-end labeling in their granulosa cells were classified atretic. The percentage of atretic follicles increased (p < or = 0.05) from 5% on Days 3 and 5 to 41% on Day 7. Expression of Ki-67 in granulosa cells was more strongly (p < or = 0.05) associated with nonatretic follicles (98% expressing) than with atretic follicles (41% expressing). Aromatase cytochrome P450 (P450arom) was localized predominantly in granulosa cells of nonatretic follicles and was undetectable in atretic follicles. Androgen receptor in granulosa cells and expression of P450 17 alpha-hydroxylase/C17-20 lyase (P450c17) in theca interna were lower (p < or = 0.001) in atretic follicles than in nonatretic follicles. The expression of 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) was localized to the theca interna and was unaffected by follicle atresia. In nonatretic small follicles, the expression of P450arom and P450c17 decreased (p < 0.01) between Days 3 and 7 while expression of Ki-67 was unchanged. In nonatretic follicles, increased follicle size was associated with a decrease (p < 0.01) in androgen receptor expression and increases (p < 0.01) in P450arom, P450c17, and 3 beta HSD expression. In conclusion, increased expression of steroidogenic enzymes was associated with follicular growth. Loss of P450arom expression in vivo is an early event in atresia and is followed by decreased cell proliferation, and decreased expression of androgen receptor and P450c17.
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PMID:Expression of androgen receptors and steroidogenic enzymes in relation to follicular growth and atresia following ovulation in pigs. 890 4


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