Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cadmium (Cd) is one of the environmental pollutants affecting various tissues and organs including testis. Harmful effect of Cd in testis is known to be germ cell degeneration and impairment of testicular steroidogenesis. Animals treated with high doses of Cd (0.2 and 0.3 mg/100g BW) showed a significant decrease in serum testosterone (T) level, but a significant induction of testicular lipid peroxidation levels. TUNEL assay showed that low doses of Cd (0.13 and 0.15 mg/100g BW) exhibited typical characteristics of apoptosis while high doses of Cd caused more necrosis than apoptosis. In contrast, supplementation with ascorbic acid reduced testicular lipid peroxidation levels. Ascorbic acid supplementation restored testicular 3beta-hydroxysteroiddehydrogenase (HSD) and 17beta-HSD enzyme activities, 3beta-HSD and cytochrome P450 side chain cleavage (P450(scc)) mRNA levels and serum T concentration to normal in Cd-administered rats. Moreover, administration of ascorbic acid prevented germ cell apoptosis as demonstrated by the reduced number of TUNEL-positive cells in germinal epithelium and inhibited Cd-induced necrosis. These results indicate that ascorbic acid have protective roles in vivo on the Cd-induced overall testicular damage including impaired steroidogenesis and germ cell death possibly through scavenging the reactive oxygen species generated by Cd administration.
Mol Cell Endocrinol 2004 Jun 30
PMID:Effect of ascorbic acid supplementation on testicular steroidogenesis and germ cell death in cadmium-treated male rats. 1522 32

Granulosa cells of small follicles differentiate in vitro in serum-free medium, resulting in increased estradiol secretion and abundance of mRNA encoding cytochrome P450aromatase (P450arom). We tested the hypothesis that differentiation in vitro also involves increased expression of 3beta- and 17beta-hydroxysteroid dehydrogenases (HSD) in the absence of steroidogenic acute regulatory protein (StAR) expression, as has been observed in vivo. Granulosa cells from small (<6 mm diameter) follicles were cultured for up to 6 days, and mRNA levels quantified by Northern hybridization or RT-PCR. Estradiol and progesterone concentrations in medium increased with time in culture, as did mRNA encoding P450arom, 3beta- and 17beta-HSD but not P450scc. Both P450arom and 17beta-HSD were significantly correlated with estradiol accumulation in culture medium. Progesterone secretion was correlated with 3beta-HSD but not P450scc mRNA levels. StAR mRNA was detectable by RT-PCR, did not change with duration of culture and was not correlated with progesterone secretion. FSH significantly stimulated P450arom and 17beta-HSD mRNA levels. Cell origin (from the antral or the basal layer of the membrana granulosa) did not affect steroidogenesis. We conclude that under the present cell culture system granulosa cells do not luteinize, and show expression of key steroidogenic enzymes in patterns similar to those occurring in differentiating follicles in vivo. Further, the data suggest that 17beta-HSD may be as important as P450arom in regulating estradiol secretion, and that 3beta-HSD is more important than P450scc as a regulator of progesterone secretion in non-luteinizing granulosa cells.
Mol Cell Endocrinol 2004 Aug 31
PMID:Expression of 17beta- and 3beta-hydroxysteroid dehydrogenases and steroidogenic acute regulatory protein in non-luteinizing bovine granulosa cells in vitro. 1527 10

The two highly related signal transducers and activators of transcription (Stats), Stat5a and Stat5b, are major mediators of prolactin signaling in both the mammary gland and in the ovary. Deficiencies in Stat5b, or in both Stat5a and Stat5b, result in loss of pregnancy during midgestation and are correlated with an increase in ovarian 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) and a decrease in serum progesterone, which normally declines only immediately before parturition. To determine the relative contribution of 20alpha-HSD to progesterone metabolism and Stat5 function during pregnancy and parturition, we created a 20alpha-HSD-deficient strain of mice by gene disruption. Mice deficient for 20alpha-HSD sustain high progesterone levels and display a delay in parturition of several days demonstrating that 20alpha-HSD regulates parturition downstream of the prostaglandin F2alpha receptor in an essential and nonredundant manner. Moreover, 20alpha-HSD deficiency partially corrected the abortion of pregnancies associated with Stat5b deficiency, supporting the concept that prolactin activation of Stat5b is important in suppressing 20alpha-HSD gene expression and thereby allowing the maintenance of progesterone levels that are required to sustain pregnancy.
Mol Endocrinol 2005 Feb
PMID:Regulation of progesterone levels during pregnancy and parturition by signal transducer and activator of transcription 5 and 20alpha-hydroxysteroid dehydrogenase. 1547 42

Ascidians have been employed as model organisms in investigating spermatogenesis. 17beta-hydroxysteroid dehydrogenase (HSD) is a steroidogenic enzyme essential for invertebrate spermatogenesis. A homologue of HSD was found in the EST database of Ciona intestinalis and cloned. Sequence analysis showed significant homology to zebra fish, sea urchin and human 17beta-HSD. The gene has an open reading frame (ORF) of 918 nucleotides coding for a polypeptide of 306 amino acids and a calculated mass of 35-kDa. Immunoblotting with an antibody raised against HSD recognized a 35-kDa protein purified from the C. intestinalis testis. The HSD protein was localized in steroidogenic cells in the Ciona testis. These results suggest that C. intestinalis 17beta-HSD is equivalent to the enzyme of vertebrate Leydig cells and that 17beta-HSD could be a phylogenetic marker for organisms producing steroids.
Mol Cells 2004 Oct 31
PMID:Expression of 17beta-hydroxysteroid dehydrogenease in testis of the ascidian Ciona intestinalis [corrected]. 1552 92

The steroids allopregnanolone and allotetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC) are positive allosteric modulators of GABA(A) receptors, generated by the reduction of 5alpha-dihydroprogesterone (5alpha-DHP) and 5alpha-DHDOC, respectively, under the catalysis of human type 3 3alpha-hydroxysteroid dehydrogenase (HSD). However, brain enzymes catalyzing the conversion of such tetrahydrosteroids back to the corresponding 5alpha-dihydrosteroids remain to be identified. Characterization of human type 10 17beta-HSD provides a new insight into its importance for the oxidation of steroid modulators of GABA(A) receptors. The apparent catalytic efficiency (k(cat)/K(m)) of this enzyme for the oxidation of allopregnanolone and 3alpha,5alpha-THDOC are 432 and 1381 min(-1) mM(-1), respectively. This enzyme has negligible 3-ketosteroid reductase activity for 5alpha-DHP and 5alpha-DHDOC even in an acidic environment. Immunoreactivity against 17beta-HSD10 was found in a number of neuronal populations. Taken together, evidence suggests that 17beta-HSD10 is the brain enzyme capable of catalyzing the oxidation of steroid modulators of GABA(A) receptors.
Mol Cell Endocrinol 2005 Jan 14
PMID:Type 10 17beta-hydroxysteroid dehydrogenase catalyzing the oxidation of steroid modulators of gamma-aminobutyric acid type A receptors. 1560 35

The great majority of breast cancers are in their early stage hormone-dependent and it is well accepted that estradiol (E2) plays an important role in the genesis and evolution of this tumor. Human breast cancer tissues contain all the enzymes: estrone sulfatase, 17beta-hydroxysteroid dehydrogenase, aromatase involved in the last steps of E2 bioformation. Sulfotransferases which convert estrogens into the biologically inactive estrogen sulfates are also present in this tissue. Quantitative data show that the 'sulfatase pathway', which transforms estrogen sulfates into the bioactive unconjugated E2, is 100-500 times higher than the 'aromatase pathway', which converts androgens into estrogens. The treatment of breast cancer patients with anti-aromatases is largely developed with very positive results. However, the formation of E2 via the 'sulfatase pathway' is very important in the breast cancer tissue. In recent years it was found that antiestrogens (e.g. tamoxifen, 4-hydroxytamoxifen), various progestins (e.g. promegestone, nomegestrol acetate, medrogestone, dydrogesterone, norelgestromin), tibolone and its metabolites, as well as other steroidal (e.g. sulfamates) and non-steroidal compounds, are potent sulfatase inhibitors. In another series of studies, it was found that E2 itself has a strong anti-sulfatase action. This paradoxical effect of E2 adds a new biological response of this hormone and could be related to estrogen replacement therapy in which it was observed to have either no effect or to decrease breast cancer mortality in postmenopausal women. Interesting information is that high expression of steroid sulfatase mRNA predicts a poor prognosis in patients with +ER. These progestins, as well as tibolone, can also block the conversion of estrone to estradiol by the inhibition of the 17beta-hydroxysteroid dehydrogenase type I (17beta-HSD-1). High expressison of 17beta-HSD-1 can be an indicator of adverse prognosis in ER-positive patients. It was shown that nomegestrol acetate, medrogestone, promegestone or tibolone, could stimulate the sulfotransferase activity for the local production of estrogen sulfates. This is an important point in the physiopathology of this disease, as it is well known that estrogen sulfates are biologically inactive. A possible correlation between this stimulatory effect on sulfotransferase activity and breast cancer cell proliferation is presented. In agreement with all this information, we have proposed the concept of selective estrogen enzyme modulators (SEEM). In conclusion, the blockage in the formation of estradiol via sulfatase, or the stimulatory effect on sulfotransferase activity in combination with anti-aromatases can open interesting and new possibilities in clinical applications in breast cancer.
J Steroid Biochem Mol Biol 2005 Feb
PMID:Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer. 1586 Feb 65

Type 7 17beta-HSD catalyzes the transformation of estrone (E1) into estradiol (E2) and dihydrotestosterone (DHT) into 5alpha -androstane-3beta,17beta-diol (3beta-diol) as well as zymosterone into zymosterol. This suggests that in addition to cholesterol metabolism, the enzyme could play a critical role in estrogen-sensitive cells, since it inactivates DHT that generally shows antagonistic effect in the cells, while producing active E2 for cell proliferation. In this report, we describe the cloning and characterization of a second form of type 7 17beta-HSD (17beta-HSD7_2) that shares 95.6% identity with 17beta-HSD7_1. Using a 7.5kb genomic DNA fragment of 17beta-HSD7_1 as probe, we have obtained 7 BAC clones: three clones containing the 17beta-HSD7_1 gene and four containing the 17beta-HSD7_2 gene. The corresponding 17beta-HSD7_2 cDNA fragments of the coding region were obtained by amplification using RT-PCR and subcloned into pCMV expression vector and stably transfected into human embryonic kidney (HEK-293) cells. The overexpressed 17beta-HSD7_2 catalyzes efficiently the transformation of E1 into E2 and of DHT into 3beta-diol. Ribonuclease protection assays (RPA) indicate that 17beta-HSD7_2 is expressed in the liver, prostate, uterus and placenta. FISH mapping using the 7.5kb genomic DNA fragment as well as 2 BAC clones of each form allowed us to map the 17beta-HSD7_1 gene on chromosome band 1q23, and 17beta-HSD7_2 on band 10p11.2. These results contrast with a previous report that the 17beta-HSD7_1 gene was mapped to chromosomal band 10p11.2. This newly identified form of 17beta-HSD7 could have a significant role by modulating active hormone levels in estrogen-sensitive cells or tissues.
J Steroid Biochem Mol Biol 2005 Feb
PMID:Cloning and characterization of human form 2 type 7 17beta-hydroxysteroid dehydrogenase, a primarily 3beta-keto reductase and estrogen activating and androgen inactivating enzyme. 1586 63

There is evidence that certain phytoestrogens can inhibit key steroidogenic enzymes although most studies have been carried out on microsomal or purified enzyme preparations, some using cell lines. This study was designed to test the hypothesis that low doses of phytoestrogens, at concentrations that would be attained through the diet, could inhibit 3beta-hydroxysteroid dehydrogenase (HSD) and/or aromatase in primary cultures of human granulosa-luteal (GL) cells and that this effect was due to a decrease in the expression of these proteins. Based on published evidence, eight compounds were selected for investigation and these included the flavones apigenin and quercetin, the isoflavones genistein, biochanin A and daidzein, the lignans, enterodiol and enterolactone, and the mycotoxin zearalenone. Human GL cells were cultured for 48 h in the presence of these phytoestrogens at concentrations ranging from 0.01 to 100 microM and after addition of fresh media the conversion of pregnenolone to progesterone or androstenedione to oestradiol over a 4h period was measured. Biochanin A was the only phytoestrogen that displayed any dose-dependent inhibition of 3beta-HSD, others showing inhibition at doses >/=10 microM. Apigenin and quercetin only inhibited aromatase/17beta-HSD at high doses as did genistein, biochanin A and daidzein. The lignans had weak inhibitory effects on aromatase/17beta-HSD, whilst zearalenone showed potent inhibition at 0.1 microM. Phytoestrogens did not exert any significant effects on protein expression of 3beta-HSD or aromatase as determined by Western blots. It is concluded that steroidogenic enzymes are inhibited by phytoestrogens in primary cultures of human GL cells but these cells are less sensitive to the effects of phytoestrogens than cell-free systems. This may be due to poor lipid solubility or cellular metabolism. We have also shown for the first time that phytoestrogens do not act by inhibiting the cellular concentration of 3beta-HSD and aromatase even though exposure time would have allowed for changes in gene expression.
J Steroid Biochem Mol Biol 2005 Aug
PMID:Dose-response effects of phytoestrogens on the activity and expression of 3beta-hydroxysteroid dehydrogenase and aromatase in human granulosa-luteal cells. 1602 37

In order to elucidate the roles of 17beta-HSDs in fish gonadal steroidogenesis, three types of 17beta-HSDs (17beta-HSD1, 17beta-HSD8 and putative 17beta-HSD12) were cloned and characterized from the Nile tilapia, Oreochromis niloticus. The cloned cDNAs of 17beta-HSD type 1, 8 and 12 were 1504, 1006 and 1930 bp long, with open reading frames encoding proteins of 289, 256 and 314 aminoacids, respectively. Tissue distribution pattern analyzed by RT-PCR and Northern blot showed that 17beta-HSD1 was dominantly expressed in the ovary, while the putative 17beta-HSD12, one of the two duplicates found in fish, is a male specific enzyme and expressed exclusively in testis (detected by RT-PCR only). On the other hand, 17beta-HSD8 was expressed in the brain, gill, heart, liver, intestine, gonad, kidney and muscle of both male and female. Enzymatic assays of the three types of 17beta-HSDs were performed using recombinant proteins expressed in E. coli or HEK 293 cells. Tilapia 17beta-HSD1 expressed in E. coli had the preference for NADP(H) as cofactor and could catalyze the inter-conversion between estrone and estradiol efficiently as well as the inter-conversion between androstenedione and testosterone, but less efficiently. Tilapia 17beta-HSD8 recombinant protein expressed in HEK 293 cells could catalyze the conversion of testosterone to androstenedione, as well as the inter-conversion between estrone and estradiol. However, the putative 17beta-HSD12 expressed in E. coli or in HEK 293 cells showed no conversion to any of the four substrates tested in this study. Based on enzyme characterization and tissue distribution, it is plausible to attribute crucial roles to 17beta-HSDs in the gonadal steroidogenesis of teleosts.
J Mol Endocrinol 2005 Aug
PMID:Cloning, expression and characterization of three types of 17beta-hydroxysteroid dehydrogenases from the Nile tilapia, Oreochromis niloticus. 1608 25

The guinea pig adrenal gland, analogous to the human, possesses the capacity to synthesize C(19) steroids. In order to further understand the control of guinea pig adrenal steroidogenesis we undertook the characterization of the guinea pig 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)-isomerase (3beta-HSD) expressed in the adrenal gland. A cDNA clone encoding guinea pig 3beta-HSD isolated from a guinea pig adrenal library is predicted to encode a protein of 373 amino acid residues and 41,475Da. Ribonuclease protection assay suggests that this cDNA corresponds to the predominant, if not the sole, mRNA species detectable in total RNA from the guinea pig adrenal gland, ovary and testis. The guinea pig 3beta-HSD shows a similar affinity for both pregnenolone and dehydroepiandrosterone, and in addition, a 17beta-HSD type II-like activity was also observed. A phylogenetical analysis of the 3beta-HSD gene family demonstrates that the guinea pig is in a parallel branch to the myomorpha group supporting the hypothesis that the guinea pig lineage has branched off after the divergence among primates, artiodactyls and rodents, suggesting the paraphyly of the order rodentia.
J Steroid Biochem Mol Biol 2005 Nov
PMID:Characterization of the guinea pig 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4-isomerase expressed in the adrenal gland and gonads. 1614 18


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