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V Luu-The

Publications and source records attributed to V Luu-The.

At least 91 records · Page 5Linked to original sources
PubMed1995

Steroidal spiro-gamma-lactones that inhibit 17 beta-hydroxysteroid dehydrogenase activity in human placental microsomes.

The important enzyme 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) is known to regulate intracellular levels of biologically active steroids, namely, androgens and estrogens. In an effort to develop potent inhibitors of 17 beta-HSD for reducing the levels of active steroids, we found that steroidal spiro-gamma-lactones inhibit 17 beta-HSD activity. In this report, we describe the synthesis of 11 spiro-gamma-lactone analogs containing a steroidal C-18 or C-19 nucleus and compare their relative inhibitory effects on 17 beta-HSD activity in the human placenta microsomes that catalyze the interconversion of androgens and estrogens. To void the interaction of the cytosolic 17 beta-HSD activity that is specific for the interconversion of estrone and estradiol, we used 4-androstenedione as substrate. Analysis of the inhibitory effect exerted by these analogs on microsomal 17 beta-HSD activity indicates that spiro-gamma-lactones containing the C-18 nucleus are more potent inhibitors than C-19 nucleus analogs. The best inhibition was obtained with the phenolic spiro-gamma-lactone 7 (3-hydroxy-19-nor-17 alpha-pregna-1,3,5(10)-triene 21,17-carbolactone), which has an IC50 value of 0.27 microM, and was much lower than the competitive effect of the unlabeled substrate 4-androstenedione, which has an IC50 value of 1.40 microM. Preincubation with lactone 7 did not inactivate 17 beta-HSD activity. The results thus suggest that lactone 7 is a reversible in inhibitor. Lactone 7 is selective for microsomal 17 beta-HSD activity, as no inhibition was observed for cytosolic 17 beta-HSD activity.

17-Hydroxysteroid Dehydrogenases↗
PubMed1995

Genetic linkage mapping of the dehydroepiandrosterone sulfotransferase (STD) gene on the chromosome 19q13.3 region.

In the human liver and adrenal, there is a single hydroxysteroid sulfotransferase, which catalyzes the transformation of dehydroepiandrosterone to dehydroepiandrosterone sulfate, the most abundantly circulating steroid in humans, and also catalyzes the sulfation of a series of other 3 beta-hydroxysteroids as well as cholesterol. Dehydroepiandrosterone sulfate serves as precursor for the formation of active androgens and estrogens in several peripheral tissues, indicating that hydroxysteroid sulfotransferase plays a pivotal role in controlling the hormonal action of sex steroids by regulating their bioavailability. We recently elucidated the structure of the gene encoding hydroxysteroid sulfotransferase (STD), also designated dehydroepiandrosterone sulfotransferase, which spans 17 kb and contains six exons. The STD gene was preliminarily assigned to chromosome 19 by polymerase chain reaction (PCR) amplification of DNA from a panel of human/rodent somatic cell hybrids. To locate the STD gene, the novel biallelic polymorphism found in intron 2 was genotyped in eight CEPH reference families by direct sequencing of PCR products. Two-point linkage analysis was first performed between the latter polymorphism and chromosome 19 markers from Généthon and NIH/CEPH. The closest linkage was observed with D19S412 (Zmax = 9.23; theta max 0.038) and HRC (Zmax = 5.95; theta max 0.036), located on the 19q13.3 region. A framework map including six Généthon markers flanking the polymorphic STD gene was created by multipoint linkage analysis. Thereafter, a high-resolution genetic map of the region was constructed, yielding to the following order: qter-D19S414-D19S224-D19S420-D19S217-(APOC2++ +-D19S412)- (STD-HRC)-KLK-D19S22-D19S180-PRKCG-D19S418 -tel.

Base Sequence↗
PubMed1995

Structure-function relationships and molecular genetics of the 3 beta-hydroxysteroid dehydrogenase gene family.

The isoenzymes of the 3 beta-hydroxysteroid dehydrogenase/5-ene-4-ene-isomerase (3 beta-HSD) gene family catalyse the transformation of all 5-ene-3 beta-hydroxysteroids into the corresponding 4-ene-3-keto-steroids and are responsible for the interconversion of 3 beta-hydroxy- and 3-keto-5 alpha-androstane steroids. The two human 3 beta-HSD genes and the three related pseudogenes are located on the chromosome 1p13.1 region, close to the centromeric marker D1Z5. The 3 beta-HSD isoenzymes prefer NAD+ to NADP+ as cofactor with the exception of the rat liver type III and mouse kidney type IV, which both prefer NADPH as cofactor for their specific 3-ketosteroid reductase activity due to the presence of Tyr36 in the rat type III and of Phe36 in mouse type IV enzymes instead of Asp36 found in other 3 beta-HSD isoenzymes. The rat types I and IV, bovine and guinea pig 3 beta-HSD proteins possess an intrinsic 17 beta-HSD activity specific to 5 alpha-androstane 17 beta-ol steroids, thus suggesting that such "secondary" activity is specifically responsible for controlling the bioavailability of the active androgen DHT. To elucidate the molecular basis of classical form of 3 beta-HSD deficiency, the structures of the types I and II 3 beta-HSD genes in 12 male pseudohermaphrodite 3 beta-HSD deficient patients as well as in four female patients were analyzed. The 14 different point mutations characterized were all detected in the type II 3 beta-HSD gene, which is the gene predominantly expressed in the adrenals and gonads, while no mutation was detected in the type I 3 beta-HSD gene predominantly expressed in the placenta and peripheral tissues. The mutant type II 3 beta-HSD enzymes carrying mutations detected in patients affected by the salt-losing form exhibit no detectable activity in intact transfected cells, at the exception of L108W and P186L proteins, which have some residual activity (approximately 1%). Mutations found in nonsalt-loser patients have some residual activity ranging from approximately 1 to approximately 10% compared to the wild-type enzyme. Characterization of mutant proteins provides unique information on the structure-function relationships of the 3 beta-HSD superfamily.

3-Hydroxysteroid Dehydrogenases↗
PubMed1995

Characteristics of human types 1, 2 and 3 17 beta-hydroxysteroid dehydrogenase activities: oxidation/reduction and inhibition.

Following transfection of types 1, 2 and 3 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) cDNAs into transformed embryonal kidney (293) cells, we have characterized the selective directional and inhibitory characteristics of these activities. While homogenates of transfected cells could catalyze interconversion of the substrate and product, in agreement with the general belief on the activity of these enzymes, the same activities measured in intact cells, in order to better reflect the physiological conditions, showed an unidirectional reaction. Types 1 and 3 17 beta-HSD catalyzed the reduction of estrone to estradiol and 4-androstenedione to testosterone, respectively, while type 2 17 beta-HSD catalyzed the oxidative transformation of both testosterone and 17 beta-estradiol to 4-androstenedione and estrone, respectively. In addition, types 1, 2 and 3 17 beta-HSD activities showed different pH optima. While types 1 and 3 showed pH optimum values centered at around 5 and 6, respectively, type 2 17 beta-HSD activity, which preferentially, catalyzes the oxidation reaction, has higher activity at an alkaline pH (8-10). Differences in the optimum incubation temperatures were also observed: type 1 17 beta-HSD shows a relatively high temperature tolerance (55 degrees C). In contrast, type 2 and 3 functioned best at 37 degrees C. Types 1, 2 and 3 17 beta-HSD activities could be also differentiated by their sensitivity toward various specific inhibitors: type 1 was potently inhibited by an estradiol derivative containing a bromo/or iodopropyl group at position 16 alpha. On the other hand a derivative of estrone containing a spiro-gamma-lactone at position 17 showed a potent inhibitory effect on type 2 17 beta-HSD, whereas type 3 was strongly inhibited by 1,4-androstadiene-1,6,17- trione.

17-Hydroxysteroid Dehydrogenases↗
PubMed1995

Structural characterization and expression of the human dehydroepiandrosterone sulfotransferase gene.

Dehydroepiandrosterone sulfotransferase catalyzes the transformation of dehydroepiandrosterone to dehydroepiandrosterone sulfate, the most abundant steroid in circulation in the human and primate. Dehydroepiandrosterone sulfate serves as precursor for the formation of active androgens and estrogens in peripheral target tissues. In addition, blockade at the dehydroepiandrosterone level could give raise to high level of DHEA and thus disorders due to mild excess of androgen. Recently, the cDNA encoding dehydroepiandrosterone sulfotransferase has been isolated from a human liver cDNA library. To study the regulation and expression, as well as the possible defect linked to DHEA sulfotransferase gene, we have isolated and characterized its structure by screening a lambda EMBL3 library of human leukocyte genomic DNA using human dehydroepiandrosterone sulfotransferase cDNA as a probe. Sequencing of the gene shows that it is included in approximately 17 kb and contains six exons separated by five introns. Northern blot analysis shows a strong signal in the adrenals and liver, whereas no signal was detected in the spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocytes, heart, brain, placenta, lung, skeletal muscle, kidney, or pancreas. Using primer extension analysis, the transcription start site is located at nucleotide 98 upstream from the ATG initiating codon. Putative TATA and CAAT boxes are situated at positions 72 and 96 upstream from the transcription start site, respectively. Using DNA from a panel of human/rodent somatic cell hybrids, and amplification of the gene by the polymerase chain reaction, the human dehydroepiandrosterone sulfotransferase gene has been assigned to chromosome 19.

Amino Acid Sequence↗
PubMed1995

Cations inhibit specifically type I 5 alpha-reductase found in human skin.

Steroid 5 alpha-reductase catalyzes the reduction of testosterone into the very potent androgen dihydrotestosterone. Previously, we showed that human type I 5 alpha-reductase is expressed mainly in the skin, whereas a type II 5 alpha-reductase is more specifically expressed in the prostate. To assess the possible differential effects of various cations on the two types of 5 alpha-reductase, we constructed expression vectors and transfected them into SW-13 cells, a human adrenal carcinoma cell line containing negligible endogenous 5 alpha-reductase activity. The expressed 5 alpha-reductases were analyzed for their sensitivity to Li, Ca, Cd, Cu, Mg, Mn, Ni, Zn, and Fe. The results showed that type I 5 alpha-reductase was strongly inhibited by Cd, Cu, and Zn and moderately inhibited by Ni and Fe, with 50% inhibitory concentration values of 0.9, 1.9, 2.0, 169.2, and 174.3 microM, respectively. In contrast, type II 5 alpha-reductase activity was inhibited only by Cu, with a 50% inhibitory concentration value of 19.2 microM. The data showed that cations could specifically control 5 alpha-reductase activity expression, which is more strongly inhibited in a target tissue, especially the skin.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1995

Genetic linkage mapping of HSD3B1 and HSD3B2 encoding human types I and II 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase close to D1S514 and the centromeric D1Z5 locus.

The enzyme 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyses an essential step in the biosynthesis of all steroid hormones. Consequently, classical 3 beta-HSD deficiency is responsible for a severe form of congenital adrenal hyperplasia. The HSD3B1 and HSD3B2 genes encoding the types I and II 3 beta-HSD isoenzymes, respectively, have been previously assigned by in situ hybridization to the chromosome 1p13.1 region. To determine the physical distance between these two genes, NotI and SacII digests of genomic DNA were resolved by pulse-field gel electrophoresis and hybridized with type I and type II 3 beta-HSD cDNAs used as probes. The detection of a single band under low stringency conditions indicates that HSD3B1 and HSD3B2 are located within an approximately 0.29 megabase SacII DNA fragment. We constructed a high resolution genetic map of the region flanking the polymorphic HSD3B1 and HSD3B2 genes including ten Généthon markers and the two NIH/CEPH markers AMY2B and D1Z5. The HSD3B1A and HSD3B2A markers were mapped relative to other reference markers through eight CEPH reference families. The order of polymorphic genes and markers is: pter-[AMY2B-D1S239]-D1S457-D1S502-D1S250-+ ++D1S252-[HSD3B1A -HSD3B2A-D1S514]-[D1Z5-D1S442]-D1S305-D 1S303-D1S484-qter. The D1S514 marker was thus closely linked to HSD3B1A (theta < 0.001; lod = 14.13) and HSD3B2 (theta = 0.008; lod = 35.36). The HSD3B loci are located 1-2 cM of the centromeric marker D1Z5.

Animals↗
PubMed1995

Overlapping cis-acting elements located in the first intron of the gene for type I 3 beta-hydroxysteroid dehydrogenase modulate its transcriptional activity.

High levels of expression for the gene encoding human type I 3 beta-hydroxysteroid dehydrogenase (3 beta-HSDI) have been detected in placenta and skin but not in adrenals, which, however, express high levels of type II 3 beta-HSD. In this study, we addressed the issue of whether the differential pattern of cell-specific expression for type I 3 beta-HSD can be explained by the differential utilization of cis-acting regulatory elements present in the 3 beta-HSDI gene regulatory sequences. Deletion analyses indicated that removal of intron 1 strongly impaired the transcriptional activity directed by the 3 beta-HSDI basal promoter. Consequently, we focused our attention to the characterization of the 128 base pair first intronic sequence from the 3 beta-HSDI gene. A single protected region, designated the 3 beta I-A element, was identified by DNase I footprinting. Gel mobility shift assays indicated that at least four nuclear proteins with distinct biochemical and binding properties possess the ability to bind the 3 beta I-A element to produce four DNA-protein complexes (R1 to R4). However, the one producing R1, a 37-kilodalton protein that has been found in both human choriocarcinoma JEG-3 and adrenal cortex adenocarcinoma SW13 cells, as well as in all tested tissue culture cells, clearly accounts for the major 3 beta I-A-binding species. Site-directed mutagenesis provided the evidence that the 3 beta I-A element acts positively on the 3 beta-HSD-I gene promoter-mediated transcriptional activity upon transient transfection of both JEG-3 and SW13 cells. No homology has been found between the 3 beta I-A element and target sequences for other known transcription factors. In addition, of the four proteins binding the 3 beta I-A element, that producing R2 was identified as the positive transcription factor Sp1, whereas the identity of the remaining factors is still unknown. This is consistent with the presence of an Sp1 motif overlapping the 3 beta I-A element in intron 1, therefore pointing toward an important function played by this particular region in 3 beta-HSDI basal, but not cell-specific, gene expression.

3-Hydroxysteroid Dehydrogenases↗
PubMed1995

["Intracrinology". Autonomy and freedom of peripheral tissues].

Hormone-sensitive cancers, namely those of the prostate, breast and uterus, constitute one third of all cancers. In addition to the classical steroidogenic tissues, namely the ovaries, testes, adrenals and placenta, a large series of peripheral tissues possess all the enzymatic systems required for the formation of active androgens and estrogens from a relatively large supply of precursor steroids namely, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) provided by the adrenals. This report describes the structure, function and tissue-specific expression and regulation of the 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, 17 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase gene families as well as some information about the aromatase gene. While, so far, most therapeutical approaches have been aimed and limited at controlling steroid formation by the classical steroidogenic tissues, it is clear that major efforts should now be turned towards intracrinology in order to better understand the physiological mechanisms controlling local steroid formation in peripheral target tissues and to develop improved therapy for hormono-sensitive diseases, especially breast, prostate, and uterine cancers.

17-Hydroxysteroid Dehydrogenases↗
PubMed1994

Structure of human estrogen and aryl sulfotransferase gene. Two mRNA species issued from a single gene.

Estrone sulfate is the predominant form of estrogens found in the circulation in women and could thus serve as precursor for active estrogens in target tissues by removal of the sulfate group through the action of endogenous steroid sulfatase. Recently, we isolated a cDNA encoding human placental estrogen sulfotransferase that differs from brain aryl sulfotransferase only in the 5'-noncoding sequence. To increase our knowledge of the regulation and tissue-specific expression of sulfotransferase gene, we screened a lambda EMBL3 library of human leucocyte genomic DNA using the estrogen sulfotransferase cDNA as probe and isolated a clone containing almost the whole gene sequence. Sequencing of the gene indicates that it is included in approximately 7.7 kilobases and contains nine short exons separated by eight introns. The two first exons, named exon 1a and exon 1b, are noncoding and correspond to the 5'-untranslated sequences of human brain and human placental estrogen sulfotransferase cDNAs, respectively. Transfection of chloramphenicol acetyltransferase reporter gene vectors containing the 5'-flanking sequence upstream from exon 1a and exon 1b in human adrenal adenocarcinoma cells indicates that both sequences possess promoter activity. The present results thus indicate that brain aryl sulfotransferase and placental human placental estrogen sulfotransferase mRNA species are transcribed from a single gene by alternate exon 1a and exon 1b promoters, respectively. Using DNA from panels of human/rodent somatic cell hybrids and amplification of the gene by polymerase chain reaction, the human placental estrogen sulfotransferase gene was assigned to chromosome 16.

Adenocarcinoma↗
PubMed1994

Localization of 3 beta-hydroxysteroid dehydrogenase in rat brain as studied by in situ hybridization.

Recent evidence suggests that brain cells can synthesize steroids de novo. The steroidogenic enzyme 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) gene family of enzymes is involved in the biosynthesis of all classes of active steroids. In the present study, we have used in situ hybridization performed with a 35S-labeled cDNA-encoding rat type I 3 beta-HSD to localize the expression of member(s) of this gene family in the adult rat brain. A specific hybridization signal could only be detected in a restricted area of the medulla ventrally and laterally bordering the fourth ventricle. This area contains the nucleus propositus hypoglossi as well as some vestibular nuclei: the nucleus vestibularis medialis, the nucleus vestibularis lateralis, and the nucleus vestibularis spinalis. At high resolution, the silver grains representing a hybridization signal were detected exclusively in neurons. The present data strongly suggest that a restricted population of neurons might be involved in steroid biosynthesis in the adult rat brain. The role of the member(s) of the rat 3 beta-HSD family in the nuclei of two cranial nerves remains to be investigated.

3-Hydroxysteroid Dehydrogenases↗
PubMed1994

Immunocytochemical localization of 5 alpha-reductase in rat brain.

The presence of steroid 5 alpha-reductase in brain tissue is well-documented. In order to determine with precision the brain areas and nerve cell types containing this enzyme in adult rat, we have studied its immunocytochemical localization using antibodies to the sequence peptide comprising amino acids 227 to 240 of the enzyme. At the light microscopic level, 5 alpha-reductase immunoreactive material appeared to be present only in glial and ependymal cells, including tanycytes. Immunolabeled cells were found in high concentration in the hypothalamus, thalamus, hippocampus, cerebral cortex, cerebral cortex, and circumventricular organs. Immunoelectron microscopic studies demonstrated that immunoreactive material was diffusely distributed throughout the cytoplasm of glial and ependymal cells, thus confirming the association of 5 alpha-reductase immunoreactivity with nonneuronal cells. These data suggest that glial cells play an important role in the conversion of testosterone to dihydrotestosterone or progesterone to dihydroprogesterone under in vivo conditions in adult rat.

Animals↗
PubMed1994

Cloning and expression of cDNA encoding human placental estrogen sulfotransferase.

Using two oligoprimers derived from the bovine placental estrogen sulfotransferase sequence, we amplified a probe for human placental estrogen sulfotransferase. Using this probe to screen a human placental cDNA library constructed in lambda gt11, we isolated a cDNA clone of 1.3 kb encoding human estrogen sulfotransferase. DNA analysis predicts a protein of 295 amino acids with a calculated molecular weight of 34,199. Alignment of the amino acid sequence with other sulfotransferases indicates that human placental estrogen sulfotransferase shares 68.6, 68.2 and 65.9% similarity with bovine placental, guinea pig adrenocortical, and rat liver estrogen sulfotransferase, respectively. It shows also 95.6, 57.6, 85.3, and 54.2% similarity to human phenol, human DHEA, rat phenol, and rat hydroxysteroid sulfotransferase, respectively. Transfection of expression vectors encoding human estrogen sulfotransferase and dehydroepiandrosterone (DHEA) sulfotransferase in human adrenal adenocarcinoma SW-13 cells indicates that estrogen sulfotransferase transforms estrone more specifically, whereas DHEA sulfotransferase is more specific for DHEA and pregnenolone.

Adenocarcinoma↗
PubMed1994

Inhibition of steroidogenesis by luteal cells of early pregnancy in the rat in response to in vitro administration of a gonadotropin-releasing hormone agonist.

Previous studies from this laboratory have demonstrated that the administration of a gonadotropin-releasing hormone agonist (GnRH-Ag) in vivo in early or mid-pregnancy to rats induces antifertility effects by suppressing the luteal production of progesterone (P4) within 24h with a concomitant increase in luteal lipid droplets and decreases in the luteal cytochrome P450 side chain cleavage (P450scc) enzyme and its mRNA content. These observations suggest a direct inhibitory effect of GnRH-Ag on the corpus luteum. Here we demonstrate a suppressive effect of GnRH-Ag in vitro on the basal P4, pregnenolone (P5) and 20 alpha-dihydroprogesterone (20 alpha-DHP) production by luteal cells obtained during early pregnancy in rats. We further studied its effect on two key enzymes, namely P450scc and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), which participate in the conversion of cholesterol to P5 and conversion of P5 to P4, respectively. We observed that two doses of GnRH-Ag, 10(-4) and 10-7 M, suppress the basal P4 production in vitro after 12 h of incubation by luteal cells; P4 remained suppressed after 48 h of incubation. Basal P5 production was also suppressed after luteal cells were incubated for 12 h with 10(-4) M and 10(-7) M GnRH-Ag, but incubation for 48 h with GnRH-Ag failed to alter P5 production by these cells. 20 alpha-DHP production was suppressed after incubating the luteal cells with both doses of GnRH-Ag for 12 h. GnRH-Ag inhibited P450scc activity after 12 h of incubation and 3 beta-HSD protein content at all time periods measured. These results suggest that GnRH exerts a direct inhibitory effect on luteal steroidogenesis. This inhibition is due to its suppressive effect on P450scc and/or 3 beta-HSD and not due to an increase in P4 metabolites.

20-alpha-Dihydroprogesterone↗
PubMed1994

Structure, regulation and role of 3 beta-hydroxysteroid dehydrogenase, 17 beta-hydroxysteroid dehydrogenase and aromatase enzymes in the formation of sex steroids in classical and peripheral intracrine tissues.

In addition to the classical steroidogenic tissues, namely the ovaries, testes, adrenals and placenta, a large series of human peripheral tissues possess all the enzymatic systems required for the formation of active androgens and oestrogens from a relatively large supply of precursor steroids provided by the adrenals. This chapter describes the structure, function, tissue-specific expression and regulation of the 3 beta-HSD and 17 beta-HSD gene families as well as some information about the aromatase gene. While, so far, most therapeutic approaches have been aimed and limited at controlling steroid formation by the classical steroidogenic tissues, it is clear that major efforts should now be turned towards intracrinology in order to understand better the physiological mechanisms controlling local steroid formation in peripheral target tissues and thus be in a position to develop novel therapeutic approaches that take into account the high proportion of steroids that are made locally and are responsible for the growth and function of normal as well as cancerous tissue.

17-Hydroxysteroid Dehydrogenases↗
PubMed1994

Characterization, expression, and immunohistochemical localization of 5 alpha-reductase in human skin.

Human skin has been shown to contain a high level of 5 alpha-reductase activity, the enzyme that catalyses the conversion of the weak androgen testosterone into dihydrotestosterone, the most potent androgen. Because two types of 5 alpha-reductase genes have been characterized in humans, we have cloned 5 alpha-reductase cDNAs from adult human keratinocyte and skin fibroblast cDNA libraries to identify and gain better knowledge of the 5 alpha-reductase expressed in normal human skin. Nucleotide sequence analysis shows that the clones obtained correspond to the type I 5 alpha-reductase. RNase protection analysis using (poly A)+ RNA obtained from human skin and prostate also confirms that type I 5 alpha-reductase is the predominant type expressed in normal skin, whereas type II 5 alpha-reductase is the major form found in the prostate. Following polymerase chain reaction amplification of human keratinocyte and skin fibroblast cDNA, a low level of type II 5 alpha-reductase cDNA has been detected. Using antipeptide antibodies raised in rabbits against the peptide sequence covering amino acids 227 -240 to perform immunohistochemical localization of 5 alpha-reductase, we have found that 5 alpha-reductase is distributed in sweat and sebaceous glands, as well as in the epidermal cell layers, thus providing the basis for the important role of androgens in human skin and its appendages.

Base Sequence↗
PubMed1994

Suppression of luteal steroidogenesis by an LHRH antagonist (Nal-Lys antagonist: antide) in vitro during early pregnancy in the rat.

LHRH and its analogues are known to exert direct effects on the ovary. Herein we have described a direct inhibitory effect of an LHRH antagonist (Nal-Lys antagonist: antide) on the basal progesterone (P4) and pregnenolone (P5) production by luteal cells obtained from the day-8 pregnant rat. Luteal cells incubated with two doses of antide (10(-4) and 10(-7) M) for 24 or 48 h showed suppression of P4 production. P5 production was suppressed by both doses of antide within 12 h of incubation. Neither dose of antide interfered with P5 production when the duration of incubation was extended beyond 12 h. The 20 alpha-dihydroprogesterone yield from the luteal cells treated with these doses of antide remained unaffected. We estimated the activities of the cholesterol side-chain cleavage (P450scc) enzyme (which is a key enzyme involved in the conversion of cholesterol to P5) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) (which catalyses the conversion of P5 to P4) in the luteal cells treated with different doses of antide. Both doses of antide suppressed the activity of the P450scc enzyme after 12 h of incubation and the 3 beta-HSD content of the luteal cells after 48 h of incubation. These observations indicate that antide exerts a direct inhibitory effect at the level of the corpus luteum, that differential suppression of P5 and P4 during different periods of incubation with antide is due to a defect in either the P450scc or the 3 beta-HSD enzyme system, or both.

20-alpha-Dihydroprogesterone↗