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Showing papers on "Hydroxysteroid dehydrogenase published in 2001"


Journal ArticleDOI
Van Luu-The1
TL;DR: The different characteristics of the multiple types of human 17beta-HSD are analyzed - types 1, 3, 5 and 7 catalyze the reductive reaction, while types 2, 4 and 8 catalyzeThe oxidative reaction, and it is noteworthy that rat type 6 17 beta- HSD also catalyzes the reaction in the oxidative direction.

259 citations


Journal ArticleDOI
TL;DR: An interesting inhibition pattern is observed for 18beta-glycyrrhetinic acid, which has no influence on the oxidative but only on the reductive reaction, which indicates that this substrate binds to pH- and cofactor-depending sites at the active center of the enzyme.

145 citations


Journal ArticleDOI
TL;DR: The double activity of type 5 17beta-HSD in the female reproductive tissues is probably necessary to the control of the optimal level of progesterone and sex steroids.

108 citations


Journal ArticleDOI
TL;DR: It is predicted that AKR1C3 catalyzes an ordered bi bi mechanism, that the rate determining step is k(chem), and that an oxyanion prevails in the transition state, and steroidal-based inhibitors that compete with the steroid product would be desirable.

104 citations


Journal ArticleDOI
TL;DR: It is demonstrated for the first time that chalcones are potent inhibitors of aromatase and 17beta-hydroxysteroid dehydrogenase activities: these enzymes being considered as important targets in the metabolic pathways of human mammary hormone-dependent cells.

98 citations


Journal ArticleDOI
TL;DR: In conclusion, progesterone regulates the conversion of biologically active E2 to estrone by inducing the 17beta-HSD type 2 enzyme in human endometrial epithelium primarily via PR in stromal cells, which secrete factors that induce transcription mediated primarily by the -200/-100 bp 5'-regulatory region of the 17 beta-HSd type 2 promoter.
Abstract: Progesterone stimulates the expression of 17β-hydroxysteroid dehydrogenase (HSD) type 2, which catalyzes the conversion of the potent estrogen, E2, to an inactive form, estrone, in epithelial cells of human endometrial tissue. Various effects of progesterone on uterine epithelium have recently been shown to be mediated by stromal PRs in mice. We describe herein a critical paracrine mechanism whereby progesterone induction of 17β-HSD type 2 enzyme activity, transcript levels, and promoter activity in human endometrial epithelial cells are mediated primarily by PR in endometrial stromal cells. Medium conditioned with progestin-pretreated human endometrial stromal cells robustly increased 17β-HSD type 2 enzyme activity (2-fold) and mRNA levels (13.2-fold) in Ishikawa malignant endometrial epithelial cells. In contrast, direct progestin treatment of Ishikawa epithelial cells gave rise to much smaller increases in enzyme activity (1.2-fold) and mRNA levels (4-fold). These results suggest that progesterone- dep...

93 citations


Journal ArticleDOI
TL;DR: It is established that in normal tissues this protein is located in mitochondria, which distinguishes it from all known 17β-hydroxysteroid dehydrogenases, and endows mitochondria with the capability of modulating intracellular levels of the active forms of sex steroids.
Abstract: The tissue distribution, subcellular localization, and metabolic functions of human 17β-hydroxysteroid dehydrogenase type 10/short chain l-3-hydroxyacyl-CoA dehydrogenase have been investigated. Human liver and gonads are abundant in this enzyme, but it is present in only negligible amounts in skeletal muscle. Its N-terminal sequence is a mitochondrial targeting sequence, but is not required for directing this protein to mitochondria. Immunocytochemical studies demonstrate that this protein, which has been referred to as ER-associated amyloid β-binding protein (ERAB), is not detectable in the ER of normal tissues. We have established that protocols employed to investigate the subcellular distribution of ERAB yield ER fractions rich in mitochondria. Mitochondria-associated membrane fractions believed to be ER fractions were employed in ERAB/Aβ-binding alcohol dehydrogenase studies. The present studies establish that in normal tissues this protein is located in mitochondria. This feature distinguishes it from all known 17β-hydroxysteroid dehydrogenases, and endows mitochondria with the capability of modulating intracellular levels of the active forms of sex steroids.

64 citations


Journal ArticleDOI
TL;DR: The results lead to the conclusion that 17beta-HSD7 is not only involved in estradiol production but plays another (and possibly more important) role as a 3-ketosteroid reductase in cholesterogenesis.

61 citations


Journal ArticleDOI
TL;DR: The ability of some these SDRs to access retinol bound with CRBP provides specificity in retinoid metabolism and allows retinoic acid biosynthesis andretinol esterification to continue, as CRBP protects retinols from the general cellular milieu.

56 citations


Journal ArticleDOI
TL;DR: From this comparative study, the best inhibitors of type II 17β-HSD (oxidase activity) were identified, but none of them were clearly more potent than the hydroxylated (reduced) forms of enzyme substrates, E2, T, and DHT.

56 citations


Journal ArticleDOI
TL;DR: The first crystallographic structure of human type 3 3α-hydroxysteroid dehydrogenase (3α-HSD3, AKR1C2), an enzyme playing a critical role in steroid hormone metabolism, has been determined in complex with testosterone and NADP at 1.25-Å resolution.

Journal ArticleDOI
TL;DR: The 17β-hydroxysteroid dehydrogenases (17HSDs) catalyze the interconversions between high-activity 17-hydroxylsteroids and low-active 17-ketosteroids as mentioned in this paper, which is essential for gonadal sex steroid biosynthesis and also involved in the modulation of steroid hormone action in peripheral tissues.

Journal ArticleDOI
Georges Pelletier1, Van Luu-The, M El-Alfy, S Li, Fernand Labrie 
TL;DR: The present data on the localization of two steroidogenic enzymes leading to the synthesis of testosterone indicate that these enzymes are located not only in epithelial cells but also in stromal and endothelial cells in both tissues studied.
Abstract: The subcellular distribution of steroidogenic enzymes has so far been studied mostly in classical endocrine glands and in the placenta. In the peripheral intracrine organs which synthesize sex steroids there is no indication about the organelles which contain the enzymes involved in steroid biosynthesis. We have thus investigated the subcellular localization of two enzymes involved in the production of sex steroids, namely 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and type 5 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Using specific antibodies to these enzymes, we conducted immunoelectron microscopic studies in two peripheral tissues, namely the human prostate and mammary gland. In the prostate, immunolabelling for both 3beta-HSD and type 5 17beta-HSD was detected in the basal cells of the tube-alveoli as well as in fibroblasts and endothelial cells lining the blood vessels. In all the labelled cell types, the gold particles were distributed throughout the cytoplasm. No obvious association with any specific organelle could be observed, although some concentration of gold particles was occasionally found over bundles of microfilaments. In mammary gland sections immunolabelled for 3beta-HSD or type 5 17beta-HSD localization, labelling was observed in the cytoplasm of the secretory epithelial cells in both the acini and terminal ducts. Immunolabelling was also found in the endothelial cells as well as in fibroblasts in stroma and blood vessels. The gold particles were not detected over any organelles, except with the occasional accumulation of gold particles over microfilaments. The present data on the localization of two steroidogenic enzymes leading to the synthesis of testosterone indicate that these enzymes are located not only in epithelial cells but also in stromal and endothelial cells in both tissues studied. The absence of any association of the enzymes with membrane-bound organelles appears as a common finding in the reactive cell types of two peripheral tissues.

Journal ArticleDOI
TL;DR: A new immunopurified polyclonal antibody, RAH113, is used to localize 11βHSD1 at the light and electron microscopy levels in a wide range of rat tissues, finding staining in the liver was of highest intensity around the central vein and decreased radially.
Abstract: The 11β-hydroxysteroid dehydrogenase type I enzyme (11βHSD1) converts cortisone to cortisol in humans, and 11-dehydrocorticosterone to corticosterone in rodents. In the present study we used a new immunopurified polyclonal antibody, RAH113, to localize 11βHSD1 at the light and electron microscopy levels in a wide range of rat tissues. 11βHSD1 staining in the liver was of highest intensity around the central vein and decreased radially. In the lung, 11βHSD1 was found at highest levels in the interstitial fibroblast, with levels in the type II pneumocyte an order of magnitude lower. RAH113 stained proximal tubules of the renal cortex and interstitial cells of the medulla and papilla. Adrenal 11βHSD1 was confined to the glomerulosa and medulla, whereas the glucocorticoid-inactivating hydroxysteroid dehydrogenase isoform 11βHSD2 was present in fascilulata/reticularis. 11βHSD1 was found in parietal cells of the fundic region of the stomach, but not in the antrum. In the heart, 11βHSD1 was detected in cells res...

Journal ArticleDOI
01 Nov 2001-Steroids
TL;DR: To develop inhibitors of type 1 17beta-HSD activity, it is hypothesized that molecules containing both hydrophobic and hydrophilic components should be interesting candidates for interacting with both the steroid binding domain and some amino acid residues of the cofactor binding domain of the enzyme.

Journal ArticleDOI
TL;DR: A significantly higher mRNA concentration in the subcortical white matter than in the cerebral cortex of women and men and reductive 17beta-HSD in vitro activity with 2 microM androstenedione as the substrate revealed no sex specific differences.

Journal ArticleDOI
TL;DR: The luteolytic effect of LH is mediated by a drop in StAR and 3β-HSD expression without effect on P450scc expression, the first in vivo evidence indicating that a decrease in luteal progesterone content may be an essential step toward the induction of 20α- HSD expression at the end of pregnancy in rats.
Abstract: A decrease in serum progesterone at the end of pregnancy is essential for the induction of parturition in rats. We have previously demonstrated that LH participates in this process through: 1) inhibiting 3β-hydroxysteroid dehydrogenase (3β-HSD) activity and 2) stimulating progesterone catabolism by inducing 20α-hydroxysteroid dehydrogenase (20α-HSD) activity. The objective of this investigation was to determine the effect of LH and progesterone on the luteal expression of the steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage (P450scc), 3β-HSD, and 20α-HSD genes. Gene expression was analyzed by Northern blot analysis 24 and 48 h after administration of LH or vehicle on Day 19 of pregnancy. StAR and 3β-HSD mRNA levels were lower in LH-treated rats than in rats administered with vehicle at both time points studied. P450scc mRNA levels were unaffected by LH. The 20α-HSD mRNA levels were not different between LH and control rats 24 h after treatment; however, greater e...

Journal ArticleDOI
TL;DR: Reconstitution experiments with recombinant protein reveal that substitution of tyrosine for cysteine at position 268 of 17β-HSD type 3 abrogates the enzymatic activity, bringing to 20 the number of mutations in the HSD17B3 gene that cause male undermasculinization.
Abstract: The 17β-hydroxysteroid dehydrogenase (HSD) type 3 isozyme catalyzes the conversion of androstenedione to testosterone in the testis. Deleterious mutations in the HSD17B3 gene cause undermasculinization in genetic males attributable to impaired testosterone biosynthesis. Hence, a hallmark of this autosomal recessive disorder is a decreased plasma testosterone-to-androstenedione ratio. Here, a novel C268Y substitution mutation in exon 10 of the HSD17B3 gene, in a subject with 17β-HSD 3 deficiency, is reported. Reconstitution experiments with recombinant protein reveal that substitution of tyrosine for cysteine at position 268 of 17β-HSD type 3 abrogates the enzymatic activity. This finding brings to 20 the number of mutations in the HSD17B3 gene that cause male undermasculinization.

Journal ArticleDOI
TL;DR: One of them, the 3β-(N-heptanoyl- l -phenylalanine- l-leucine-aminomethyl)-3α-hydroxy-5α-androstan-17-one (42) inhibited the enzyme with an IC50 value of 227 nM, which is twice as potent as the natural substrate Δ4-dione when used itself as an inhibitor.

Journal ArticleDOI
TL;DR: The results suggest that Japanese eel ovarian 20β-HSD is composed of membrane-bound and soluble activities, and that the membrane- bound component is stimulated by gonadotropin.

Journal ArticleDOI
TL;DR: Rat testis microsomal 17β-HSD showed that it differed from the human enzyme mainly in its greater ability to accept oestrone as substrate and the pH-optimum for oxidation of testosterone, so negating it use as a more readily available tissue for the screening of potential inhibitors.
Abstract: In a screening programme for inhibitors of human testis 17β-hydroxysteroid dehydrogenase (17β-HSD type 3), as potential agents for the treatment of hormone-dependent prostatic cancer, we have used crude human testis microsomal 17β-hydroxysteroid dehydrogenase as a convenient source of the enzyme. Crude human enzyme was shown to have a similar substrate profile to recombinant Type 3 17β-HSD from the same source as determined by the low Km/Vmax ratio for the reduction of androste-nedione compared to the oxidation of testosterone, and a low level of activity in reduction of oestrone. Screening of a wide range of compounds of different structural types as potential inhibitors of the microsomal enzyme in the reduction step revealed that certain p-benzoquinones and flavones/isoflavones were potent inhibitors of the enzyme, diphenyl-p-benzoquinone (2.7 μM), phenyl-p-benzoquinone (5.7 μM), 7-hydroxyflavone (9.0 μM), baicalein (9.3 μM) and biochanin A (10.8 μM). Some structure-activity relationships within the fla...

Book ChapterDOI
TL;DR: The findings suggest that disturbance of steroid hormone homeostasis by high level of brain 17ý-HSD10, rather than is binding of Aý, underlies the involvement of this protein in Alzheimer’s disease.
Abstract: Human type 10 17s-hydroxysteroid dehydrogenase (17s-HSD10) is a multifunctional enzyme1. It displays L-3-hydroxyacyl-CoA dehydrogenase activity2and belongs to the short chain dehydrogenase family3, and thus was previously designated as short chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD). This protein has a high affinity for amyloid-s peptide and was reportedly localized at the endoplasmic reticulum, and for that reason it was formerly known as endoplasmic reticulum-associated amyloid-s peptide-binding protein (ERAB)4. We provide evidence that 17s-HSD10 is a nuclear gene-encoded mitochondrial enzyme. It is the only brain 17s-HSD known as yet able to modulate intracellular estrogen levels in a brain region susceptible to AD pathology. The findings suggest that disturbance of steroid hormone homeostasis by high level of brain 17ý-HSD10, rather than is binding of Aý, underlies the involvement of this protein in Alzheimer’s disease.

Journal ArticleDOI
TL;DR: Expression studies revealed that 17beta-HSDcl is mainly expressed in the stationary phase of growth indicating its possible involvement in secondary metabolism.

Journal ArticleDOI
TL;DR: In this paper, the evolutionary relationship among 17β-hydroxysteroid dehydrogenase (17β-HSDcl), fungal reductases, versicolorin reductase (Ver1), trihydroxynaphthalene reductes (THNR), and other homologous proteins was examined.

Journal ArticleDOI
TL;DR: This review analyzes data on the biological role of 3α-hydroxysteroid dehydrogenase (3α-HSD) in animal and human tissues and describes its main characteristics, mechanism of action, and regulation of activity.
Abstract: This review analyzes data on the biological role of 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) in animal and human tissues and describes its main characteristics, mechanism of action, and regulation of activity. Based on published data, a scheme for the actions of androgen, progestin, and glucocorticoids involving the participation of 3alpha-HSD is proposed. According to this scheme, in the mechanism of steroid action 3alpha-HSD not only regulates the concentration of the main effector androgen, 5alpha-dihydrotestosterone, in target cells, but also switches androgen, progestin, and glucocorticosteroid genomic activity to non-genomic activity.

Journal ArticleDOI
TL;DR: In situ hybridization indicates that the expression of HSDL1 is predominantly increased in the prostate cancer tissue compared with the normal prostate tissue, which suggests that the gene expression is important to the arising of prostate cancer.
Abstract: We report the cloning and characterization of a novel human hydroxysteroid dehydrogenase like gene (HSDL1) located on human chromosome 16q24.2. The HSDL1 cDNA is 3407 base pair in length, encoding a 309 amino acid polypeptide related to human 17β-HSD3. Northern blot reveals that the HSDL1 is highly expressed in testis and ovary. In situ hybridization indicates that the expression of HSDL1 is predominantly increased in the prostate cancer tissue compared with the normal prostate tissue, which suggests that the gene expression is important to the arising of prostate cancer.

Journal ArticleDOI
TL;DR: Generally, a stronger reaction for 17β-hydroxysteroid dehydrogenase is shown with NAD as cofactor than with NADP; using NADP, fetal Leydig cells show a stronger staining than adult LeydIG cells.
Abstract: The enzyme 17β-hydroxysteroid dehydrogenase is required for the synthesis and 11β-hydroxysteroid dehydrogenase for the regulation of androgens in rat Leydig cells. This histochemical study describes ontogenetic changes in distribution and intensity of these enzymes in Leydig cells from postnatal day (pnd) 1–90. Using NAD or NADP as the cofactor, 17β-hydroxysteroid dehydrogenase (substrate: 5-androstene-3β, 17β-diol) peaks were observed on pnd 16 for fetal Leydig cells and on pnd 19 and 37 for adult Leydig cells. Between pnd 13 and 25 the fetal cells showed a higher intensity for the 17β-enzyme than the adult cells; more fetal Leydig cells were stained with NADP, whereas more adult cells were positive with NAD on pnd 13 and 16. A nearly identical distribution of 11β-hydroxysteroid dehydrogenase (substrate: corticosterone) was observed with NAD or NADP as the cofactor; the reaction was present from pnd 31 onwards, first in a few adult Leydig cells and later in almost all these cells homogeneously. The ontogenetic curves of the two enzymes show an inverse relationship. To conclude: (1) Generally, a stronger reaction for 17β-hydroxysteroid dehydrogenase is shown with NAD as cofactor than with NADP; using NADP, fetal Leydig cells show a stronger staining than adult Leydig cells. (2) The data possibly support the notion of a new isoform of 11β -hydroxysteroid dehydrogenase in addition to types 1 and 2.

Journal ArticleDOI
TL;DR: It is concluded that hCG can protect ovarian steroidogenic and gametogenic function after lithium chloride treatment, and the duration of the oestrous cycle was increased in lithium chloride-treated rat with longer metestrous and diestrous phases.

Journal ArticleDOI
TL;DR: Targeting signals for different subcellular organelles in human hydroxysteroid dehydrogenases have been identified, however, in several enzymes localization signals remain to be determined.

Journal ArticleDOI
TL;DR: Results suggest that the same molecular species as ovarian 20a-HSD is expressed in thymic lymphocytes, and may play a role in T-lymphocyte proliferation and differentiation processes.
Abstract: Ovarian 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), which converts progesterone to a derivative devoid of biological activity, plays a crucial role in achieving the short estrous cycle in rats. Although 20alpha-HSD activity has also been demonstrated in the thymus, its molecular nature, function, and regulation of expression have yet to be determined. In the present study we investigated if 20alpha-HSD activity in the thymus originates in a transcript identical to that expressed in the ovary. RT-PCR analysis indicated the expression of 20alpha-HSD mRNA in rat thymus, and sequencing of the PCR product showed 100% identity to ovarian 20alpha-HSD cDNA. Immunohistochemical study using anti-rat ovarian 20alpha-HSD antibody demonstrated the expression of 20alpha-HSD protein in the thymus. The 20alpha-HSD-expressing cells in the thymus seemed to be some type of lymphocyte by their morphology. These results suggest that the same molecular species as ovarian 20a-HSD is expressed in thymic lymphocytes. Therefore, 20alpha-HSD may play a role in T-lymphocyte proliferation and differentiation processes.