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)

Environmental anti-androgens are increasingly being recognized as potential contributing factors in the chemically induced feminization of wild fish because, by blocking androgen action, they can produce phenotypic effects similar to environmental estrogens. The molecular mechanisms by which anti-androgens and estrogens exert feminizing effects, however, have not been systematically compared. Using a targeted approach, we profiled the expression responses of a suite of 22 genes involved in reproduction, growth and development (processes controlled by androgens and estrogens) in the liver and gonad in adult male and female fathead minnow (Pimephales promelas) exposed to the model anti-androgen flutamide and the model synthetic estrogen 17alpha-ethinylestradiol (EE(2)). Both flutamide (320 microg/L) and EE(2) (10ng/L) produced phenotypic effects indicative of feminization (induction of plasma vitellogenin, reduced gonadosomatic index, and reduced secondary sex characters), although for the chosen test concentrations EE(2) was the more potent. For the genes studied, flutamide and EE(2) produced distinct expression profiles, suggesting that they largely operate via distinct molecular mechanisms. As examples, in liver EE(2) (but not flutamide) exposure up-regulated estrogen receptor (ER) alpha mRNA, whereas flutamide exposure increased ERbeta and ERgamma mRNAs in males and resulted in decreased androgen receptor (AR) mRNA in females. In the testis, flutamide up-regulated genes coding for enzymes involved in androgen biosynthesis (cytochrome P450 17 [CYP17] and 11beta-hydroxysteroid dehydrogenase [11beta-HSD]) implying an inhibitory action on androgen negative feedback pathways. EE(2), in contrast, inhibited the expression of enzymes involved in androgen biosynthesis (CYP17, 11beta-HSD and 17beta-hydroxysteroid dehydrogenase [17beta-HSD]). There were also some commonalities in the molecular mechanisms of flutamide and EE(2) action, including the down-regulation of gonadal sex steroid receptor expression (gonadal AR and ovarian ERalpha), increased expression of genes coding for estrogen-producing enzymes (cytochrome P450 19A and B [CYP19A and CYP19B]), decreased expression of genes involved in testis differentiation (anti-Mullerian hormone [AMH] and doublesex and mab-3 related transcription factor 1 [DMRT1]), and decreased expression of hepatic genes which mediate wider physiological processes such as somatic growth (growth hormone [GH], GH receptor [GHR], insulin-like growth factor-I [IGF-I], IGF-I receptor [IGF-IR], thyroid hormone receptor alpha [TRalpha] and beta [TRbeta]).
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PMID:Gene expression profiles revealing the mechanisms of anti-androgen- and estrogen-induced feminization in fish. 1722 21

Prostate cancer is a major health issue in westernized countries, being considered a prototypical age-related, androgen-dependent tumor. However, data on the association between circulating androgens and prostate cancer have been inconsistent and mostly not compatible with the androgen hypothesis. In addition, plasma androgen-to-estrogen ratio appears to decrease with age, suggesting that estrogens may also have a role. Results from our own and others' studies suggest that circulating steroids cannot be considered representative of their actual intraprostatic levels. This is a consequence of the expression and/or activity of steroid enzymes, including 17beta-hydroxysteroid dehydrogenase (17beta-HSD), 5alpha-reductase, 3alpha/3beta-HSD, and aromatase, which may eventually lead to a differential tissue accumulation of steroid derivatives having distinct biological activities. Interestingly, many of the genes encoding for steroid enzymes are highly polymorphic in nature, although only a few studies have investigated their relation with prostate cancer and the data presently available are inconclusive. Locally produced or metabolically transformed estrogens may differently affect proliferative activity of prostate cancer cells. In our studies, estrogen may either stimulate or decrease prostate cancer cell growth, also depending on the receptor status. In particular, an imbalance of ERalpha and ERbeta expression may be critical to determine the ultimate estrogen effects on prostate cancer cell growth. Furthermore, evidence is accumulating that estrogens regulate gene transcription through an array of estrogen-response elements (EREs) and non-EREs, either ligand-dependent or -independent. This is further complicated by the presence of receptor isoforms, distinct cofactor interaction, and potential heterodimerization. Based on this combined evidence, a hypothetical model of prostate cancer progression is presented.
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PMID:Estrogens and mechanisms of prostate cancer progression. 1726 68

Polychlorinated biphenyls (PCBs) are ubiquitous and persistent environmental contaminants that disturb normal endocrine functions, including gonadal functions in humans and mammals. In the present study, we examined the direct effects of PCB on rat Leydig cells in vitro. Adult Leydig cells were purified by Percoll gradient centrifugation method and the purity of Leydig cells was also determined by 3beta-hydroxysteroid dehydrogenase (3beta-HSD) staining method. Purified Leydig cells were exposed to different concentrations (10(- 10)-10(- 7) M) of PCB (Aroclor 1254) for 24 h under basal and LH-stimulated conditions. After the experimental period, cultured media were collected and used for the assay of testosterone and estradiol. The treated cells were used for the quantification of cell-surface LH receptors and activities of steroidogenic enzymes, such as cytochrome P(450) side-chain cleavage enzyme (P450scc), 3beta-HSD, and 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Leydig cellular enzymatic antioxidants, such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, gamma-glutamyl transpeptidase, glutathione-S-transferase, and nonenzymatic antioxidants, such as vitamins C and E, were assayed. Lipid peroxidation (LPO) and reactive oxygen species (ROS) were also estimated in Leydig cells. In addition, total RNA was isolated from control and Aroclor 1254-exposed Leydig cells to monitor the steady-state mRNA levels by reverse transcription(RT)-PCR for steroidogenic acute-regulatory (StAR) protein, cytochrome P450scc, 3beta-HSD, and 17beta-HSD. Our results indicated that Aroclor 1254 (10(- 9), 10(- 8), and 10(- 7) M) treatments significantly inhibit basal and LH-stimulated testosterone and estradiol production. In addition, the activities of steroidogenic enzymes, enzymatic and nonenzymatic antioxidants were significantly diminished in a dose-dependent manner. However, LPO and ROS were elevated in a dose-dependent manner under basal and LH-stimulated conditions. RT-PCR analysis of StAR mRNA level showed a decrease only in 10(- 7) M dose of Aroclor 1254 treatment, while cytochrome P(450)scc, 3beta-HSD, and 17beta-HSD mRNAs were drastically decreased in both 10(- 8) and 10(- 7) M Aroclor 1254 treatment. These findings suggest that PCBs can act directly on Leydig cells to diminish testosterone production by inhibiting gene expression of steroidogenic enzymes and antioxidant system.
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PMID:Effects of polychlorinated biphenyl (Aroclor 1254) on steroidogenesis and antioxidant system in cultured adult rat Leydig cells. 1728 32

Carbendazim (methyl-2-benzimidazole carbamate, MBC) a metabolite of benomyl is one of the most widespread environmental contaminant of major concern to human and animal reproductive health. The present investigation was undertaken to study the impact of carbendazim exposure on Leydig cell functions. Adult albino male rats of the Wistar strain were administered with carbendazim (25 mg/(kg (body weight)/day)) orally for 48 days. The control animals received vehicle (corn oil) alone. Another group of rats were treated with carbendazim and the same was withdrawn for a further period of 48 days. After the treatment period, rats were euthanized and blood was collected for the assay of serum hormones such as luteinizing hormone (LH), prolactin (PRL), testosterone and estradiol. Testes were immediately removed and Leydig cells were isolated in aseptic condition. Purified Leydig cells were used for quantification of steroidogenic enzymes such as 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Leydig cellular enzymatic antioxidants superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), gamma-glutamyl transpeptidase (gamma-GT), glucose-6-phosphate dehydrogenase (G6PDH) and non-enzymatic antioxidants such as reduced glutathione (GSH), alpha-tocopherol (vitamin E), ascorbic acid (vitamin C) and beta-carotene (vitamin A) were assayed. Lipid peroxidation (LPO) and reactive oxygen species (ROS) were also quantified. Carbendazim exposure had no effect on body weight, serum LH and prolactin. However, testis weight, serum testosterone and estradiol were significantly decreased. In addition to this, Leydig cellular activities of steroidogenic enzymes such as 3beta-HSD, 17beta-HSD, antioxidant enzymes SOD, CAT, GPx, GR, GST, gamma-GT, G-6-PDH and non-enzymatic antioxidants such as GSH, vitamins E, C and A were significantly diminished, whereas LPO and ROS were markedly elevated. All these above-mentioned parameters from the animals after withdrawal of MBC treatment were similar to those of the control group. Thus, the present study suggests that chronic low dose treatment of MBC is capable of inducing reproductive toxicity through increased oxidative stress, but is transient and reversible upon withdrawal of treatment.
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PMID:Modulation of antioxidant defense system by the environmental fungicide carbendazim in Leydig cells of rats. 1748 93

Using polyclonal antibodies, we examined the localization of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) as markers of the site of steroidogenetic activity during the spermatogenesis of Torpedo marmorata. These enzymes play a central role in the biosynthesis of steroid hormones, including androgen and oestrogen production. We demonstrated that in the spotted ray testis, Sertoli and Leydig cells, as well as spermatogonia, show a positive reaction to anti 3beta-HSD and 17beta-HSD antibodies. In particular, we demonstrated that Sertoli cells show a positive reaction to anti 3beta-HSD and 17beta-HSD antibodies in cysts containing spermatogonia and spermatozoa, while Leydig cells present a positive reaction only when they are located between cysts containing meiotic cells. This study strongly suggests that, as hypothesised in our previous study [Prisco, M., Liguoro, A., D'Onghia, B., Ricchiari, L., Andreuccetti, P., Angelini, F., 2002. Fine structure of Leydig and Sertoli cells in the testis of immature and mature spotted ray Torpedo marmorata. Mol. Reprod. Dev. 63, 192-201.], Sertoli and Leydig cells are differently involved in the hormonal control of spermatogenesis: Sertoli cells before the beginning of meiosis and after spermiation, Leydig cells only during meiosis phase. Moreover, the present paper deals with the possibility that also spermatogonia are engaged in the production of androgen hormones, as they are characterized by the presence of 3beta-HSD and 17beta-HSD enzymes, and show the ultrastructural features of steroid hormone-producing cells.
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PMID:Immunolocalization of 3beta-HSD and 17beta-HSD in the testis of the spotted ray Torpedo marmorata. 1756 Oct 19

The skin is a well-recognized site of steroid formation and metabolism. Episkin is a cultured human epidermis. In this report, we investigate whether Episkin possesses a steroidogenic machinery able to metabolize adrenal steroid precursors into active steroids. Episkin was incubated with [14C]-dehydroepiandrosterone (DHEA) and 4-androstenedione (4-dione) and their metabolites were analyzed by liquid chromatography/mass spectrometry (LC/MS/MS). The results show that the major product of DHEA metabolism in Episkin is DHEA sulfate (DHEAS) (88% of the metabolites) while the other metabolites are 7alpha-OH-DHEA (8.2%), 4-dione (1.3%), 5-androstenediol (1.3%), dihydrotestosterone (DHT) (1.4%) and androsterone (ADT) (2.3%). When 4-dione is used as substrate, much higher levels of C19-steroids are produced with ADT representing 77% of the metabolites. These data indicate that 5alpha-reductase, 17beta-hydroxysteroid dehydrogenase (17beta-HSD) and 3alpha-hydroxysteroid dehdyrogenase (3alpha-HSD) activities are present at moderate levels in Episkin, while 3beta-HSD activity is low and represents a rate-limiting step in the conversion of DHEA into C19-steroids. Using realtime PCR, we have measured the level of mRNAs encoding the steroidogenic enzymes in Episkin. A good agreement is found between the mRNAs expression in Episkin and the metabolic profile. High expression levels of steroid sulfotransferase SULT2B1B and type 3 3alpha-HSD (AKR1C2) correspond to the high levels of DHEA sulfate (DHEAS) and ADT formed from DHEA and 4-dione, respectively. 3beta-HSD is almost undetectable while the other enzymes such as type 1 5alpha-reductase, types 2, 4, 5, 7, 8, and 10 17beta-HSD and 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) (AKR1C1) are highly expressed. Except for UGT-glucuronosyl transferase, similar mRNA expression profiles between Episkin and human epidermis are observed.
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PMID:Steroid metabolism and profile of steroidogenic gene expression in Episkin: high similarity with human epidermis. 1766 97

Metyrapone, a specific inhibitor of 11beta-hydroxylase inhibits glucocorticoid production and it is used in the diagnosis/treatment of hypercortisolism and also to test the functional integrity of hypothalamo-pituitary-adrenal axis. To assess the impact of glucocorticoid deficiency, this drug is preferred over adrenalectomy, which eliminates all the hormonal secretions of the adrenal cortex and medulla. However, whether metyrapone has any direct effect on the extra-adrenocortical cellular or tissue functions remains to be resolved. Our previous study showed a depressed testicular Leydig cell testosterone production in rats treated with metyrapone. Therefore, the present study was designed to examine the possible direct effect of metyrapone on testicular Leydig cell steroidogenesis in vitro. Leydig cell viability and the reactive oxygen species (ROS) concentration were not altered by any of the concentration of metyrapone tested. The efficacy of Leydig cell testosterone production under basal as well as LH-stimulated condition was not altered by metyrapone treatment. Further, Leydig cellular (14)C-glucose oxidation, the activity and mRNA levels of cytochrome side chain cleavage (P(450)scc), 3beta- and 17beta-hydroxysteroid dehydrogenase (3beta-HSD and 17beta-HSD) were not altered in metyrapone-treated cells. Therefore, it is concluded from the present study that metyrapone has no direct effect on Leydig cell testosterone production and, therefore, changes recorded in the in vivo studies are exclusively due to corticosterone deficiency.
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PMID:Assessment of in vitro effects of metyrapone on Leydig cell steroidogenesis. 1817 8

Methoxychlor, an organochlorine pesticide, has been reported to induce reproductive abnormalities in male reproductive tract. To get more insight into the mechanism(s) of gonadal toxicity provoked by methoxychlor, we investigated whether treatment with methoxychlor at low observed adverse effect level (LOAEL) would alter the activities of steroidogenic enzymes such as Delta(5)3beta-hydroxysteroid dehydrogenase (3beta-HSD) and Delta(5)17beta-hydroxysteroid dehydrogenase (17beta-HSD), the expression levels of steroidogenic acute regulatory (StAR) protein and androgen binding protein (ABP) in the testis of adult male rats. The experimental rats were exposed to a single dose of methoxychlor (50 mg/kg body weight) orally. The rats were killed at 0, 3, 6, 12, 24 and 72 h following treatment using anesthetic ether and testes were collected, processed and used to measure the activities of 3beta-HSD, 17beta-HSD, levels of hydrogen peroxide produced and the expression levels of StAR protein, and ABP. Methoxychlor administration resulted in a sequential reduction in the expression of StAR protein and activities of 3beta-HSD, 17beta-HSD with concomitant increase in the levels of hydrogen peroxide in the testis. These changes were significant between 6-12 h following treatment. The levels of ABP declined at 6-12 h following exposure to methoxychlor. The present study demonstrates transient effect of methoxychlor at LOAEL on testicular steroidogenesis and the possible role of hydrogen peroxide in mediating these effects.
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PMID:Transient inhibitory effect of methoxychlor on testicular steroidogenesis in rat: an in vivo study. 1840 75

Polychlorinated biphenyls (PCBs) are environmental contaminants that in humans and animals disturb normal endocrine functions including gonadal functions. The present studies were aimed at determining the direct effects of PCB on Leydig cell testosterone production and antioxidant system in vitro. Adult Leydig cells were purified by Percoll gradient centrifugation method and the purity of Leydig cells was also determined by 3beta-hydroxysteroid dehydrogenase (3beta-HSD) staining method. Purified Leydig cells were exposed to different concentrations (10(-10) to 10(-7) M) of PCB (Aroclor 1254) for 6 and 12 h under basal and LH-stimulated conditions. After incubation, the cultured media were collected and used for the assay of testosterone. The treated cells were used for quantification of cell surface LH receptors and activity of steroidogenic enzymes such as cytochrome P450 side chain cleavage enzyme (P450scc), 3beta-HSD and 17beta-hydroxysteroid dehydrogenase (17beta-HSD). In addition, Leydig cellular enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), gamma-glutamyl transpeptidase (gamma-GT), glutathione-S-transferase (GST) and non-enzymatic antioxidants such as vitamin C and E were assayed. Lipid peroxidation (LPO) and reactive oxygen species (ROS) were also estimated in Leydig cells. The results indicated that Aroclor 1254 (10(-8) and 10(-7) M) treatments significantly inhibit basal and LH-stimulated testosterone production. In addition to this, the activity of steroidogenic enzymes, enzymatic and non-enzymatic antioxidants were significantly diminished in a dose- and time-dependent manner. Moreover, the LPO and ROS were elevated in a dose- and time-dependent manner under basal and LH-stimulated conditions. These findings suggest that PCBs can act directly on Leydig cells to inhibit testosterone biosynthesis by reducing steroidogenic enzymes, enzymatic and non-enzymatic antioxidants.
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PMID:Polychlorinated biphenyl (Aroclor 1254) inhibits testosterone biosynthesis and antioxidant enzymes in cultured rat Leydig cells. 1850 95

The cytochrome P450 enzyme, 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), is a potential target in hormone-dependent cancers. We report the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of azole-based compounds as inhibitors of the two components of P450(17alpha), i.e., 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results suggest that the imidazole-based compounds are highly potent inhibitors of both components, with N-7-phenyl heptyl imidazole (21) (IC(50)=0.32 microM against 17alpha-OHase and IC(50)=0.10 microM against lyase) and N-8-phenyl octyl imidazole (23) (IC(50)=0.25 microM against 17alpha-OHase and IC(50)=0.21 microM against lyase) being the two most potent compounds within the current study, in comparison to ketoconazole (KTZ) (IC(50)=3.76 microM against 17alpha-OHase and IC(50)=1.66 microM against lyase). Furthermore, consideration of the inhibitory activity against the two components show that the compounds tested are less potent towards the 17alpha-OHase component, a desirable property in the development of novel inhibitors of P450(17alpha). Structure-activity relationship determination of the range of compounds synthesised suggests that logP (log of the partition coefficient) is a key physicochemical factor in determining the overall inhibitory activity. In an effort to determine the viability of these compounds becoming potential drug candidates as well as to show specificity of these compounds, we undertook the biochemical evaluation of the synthesised compounds against two isozymes of 17beta-hydroxysteroid dehydrogenase [namely type 1 (17beta-HSD1) and type 3 (17beta-HSD3)] and 3beta-hydroxysteroid dehydrogenase (3beta-HSD). Consideration of the inhibitory activity possessed by the compounds considered within the current study against 3beta-HSD, 17beta-HSD1 and 17beta-HSD3 shows that there is no clear structure-activity relationship and that the compounds appear to possess similar inhibitory activity against both 3beta-HSD and 17beta-HSD3 whilst against 17beta-HSD1, the compounds appear to possess poor inhibitory activity at [I]=100 microM. Indeed, two of the most potent inhibitors of P450(17alpha), (compounds 21 and 23), were found to possess relatively good levels of inhibition against the three enzymes-compound 21 was found to possess approximately 32%, approximately 21% and approximately 37% inhibition whilst compound 23 was found to possess approximately 38%, approximately 30% and approximately 28% inhibition against 3beta-HSD, 17beta-HSD1 and 17beta-HSD3 respectively. We therefore concluded that the azole-based compounds synthesised within the current study are not suitable for further consideration as potential drug candidates due to their lack of specificity.
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PMID:Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of phenyl alkyl imidazole-based compounds as potent inhibitors of the enzyme complex 17alpha-hydroxylase/17,20-lyase (P450(17alpha)). 1862 55


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