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PubMed2001

Inhibitors of human and rat testes microsomal 17beta-hydroxysteroid dehydrogenase (17beta-HSD) as potential agents for prostatic cancer.

In a screening programme for inhibitors of human testis 17beta-hydroxysteroid dehydrogenase (17beta-HSD type 3), as potential agents for the treatment of hormone-dependent prostatic cancer, we have used crude human testis microsomal 17beta-hydroxysteroid dehydrogenase as a convenient source of the enzyme. Crude human enzyme was shown to have a similar substrate profile to recombinant Type 3 17beta-HSD from the same source as determined by the low Km/Vmax ratio for the reduction of androstenedione 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 microM), phenyl-p-benzoquinone (5.7 microM), 7-hydroxyflavone (9.0 microM), baicalein (9.3 microM) and biochanin A (10.8 microM). Some structure-activity relationships within the flavone/isoflavone series are discussed. Studies with rat testis microsomal 17beta-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. It was found to be much less sensitive to inhibition by the compounds studied so negating it use as a more readily available tissue for the screening of potential inhibitors.

17-Hydroxysteroid Dehydrogenases↗
PubMed1995

The human type II 17 beta-hydroxysteroid dehydrogenase gene encodes two alternatively spliced mRNA species.

The isozymes of the 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) gene family are responsible for the formation of the 17 beta-hydroxysteroids delta 5-androstene-3 beta,17 beta-diol, testosterone, 17 beta-estradiol, and dihydrotestosterone from their corresponding 17-ketosteroid precursors, thus playing a pivotal role in the formation of active sex steroids in both steroidogenic and peripheral target tissues. To clone the type II 17 beta-HSD gene, the full-length cDNA type II 17 beta-HSD was used as probe to screen a human leukocyte genomic DNA library. The type II 17 beta-HSD gene contains seven exons and spans > 40 kbp. The type II 17 beta-HSD gene encodes two alternatively spliced mRNAs that give rise to the previously identified type IIA 17 beta-HSD protein of 387 amino acids, as well as to a related 291-amino-acid type IIB 17 beta-HSD protein of unknown function. RNA blot analysis revealed the presence of a major 1.45-kb transcript that is abundant in placenta and endometrium. The mRNA cap site has been localized in a region between 179 and 167 nucleotides upstream of the ATG start codon by RNase protection and S1 nuclease mapping analyses. Cloning of the 17 beta-HSD type II gene provides us with the tools to study its transcriptional expression.

17-Hydroxysteroid Dehydrogenases↗
PubMed1988

20 beta-hydroxysteroid dehydrogenase of neonatal pig testis: purification and some properties.

20 beta-Hydroxysteroid dehydrogenase was purified from a cytosol fraction of neonatal pig testes to homogeneity as demonstrated by polyacrylamide gel electrophoresis (PAGE) and by isoelectric focusing. The molecular weight was estimated to be 30,500 using PAGE with sodium dodecyl sulfate and the gel filtration method. Molecular estimations showed that the purified enzyme consisted of a single polypeptide chain. It catalyzed the reduction of 17 alpha-hydroxyprogesterone to 17 alpha,20 beta-dihydroxypregn-4-en-3-one with NADPH. Furthermore, the C21-steroids, such as progesterone, pregnenolone, 17 alpha-hydroxypregnenolone, deoxycorticosterone, and deoxycortisol were also reduced by the purified enzyme. Apparent Km values for 17 alpha-hydroxyprogesterone, progesterone, pregnenolone, and deoxycorticosterone were 9.4, 1.5, 4.0, and 8.6 microM, respectively. The enzyme did not show 20 alpha-hydroxysteroid dehydrogenase activity. The maximum rate of enzyme activity was observed at 45 degrees C and optimum pH was at pH 5.5. The enzyme activity was strongly inhibited by heavy metal ions such as Hg2+ and Cu2+.

20-Hydroxysteroid Dehydrogenases↗
PubMed1986

3 beta-Hydroxysteroid dehydrogenase of Ruminococcus sp. from human intestinal bacteria.

Ruminococcus sp. PO1-3 obtained from human intestinal flora is able to reduce dehydrocholate as well as 3-ketoglycyrrhetinate. From this bacterium dehydrocholate- and 3-ketoglycyrrhetinate-reducing activities were purified one thousand-fold together with 3-ketocholanate-reducing and 3-beta-hydroxyglycyrrhetinate (glycyrrhetic acid) oxidizing activities by means of Matrex Red A, Sephadex G-200 and Octyl-Sepharose column chromatography. The purified enzyme catalyzed the reduction of dehydrocholic acid to 3 beta-hydroxy-7,12-diketocholanic acid and of 3-ketocholanic acid to 3 beta-hydroxycholanic acid. Studies on substrate specificity revealed that the enzyme had absolute specificity for the beta-configuration of a hydroxyl group at the 3 position of bile acid and steroids having no double bond in the A/B ring. This enzyme was neither beta-hydroxysteroid dehydrogenase [EC 1.1.1.51] nor 3 beta-hydroxy-delta 5-steroid dehydrogenase [EC 1.1.1.145], but a novel type of enzyme, defined as 3 beta-hydroxysteroid dehydrogenase.

3-Hydroxysteroid Dehydrogenases↗
PubMed2002

Dynamic changes in the expression of relaxin-like factor (INSL3), cholesterol side-chain cleavage cytochrome p450, and 3beta-hydroxysteroid dehydrogenase in bovine ovarian follicles during growth and atresia.

Relaxin-like factor (RLF) is a new member of the insulin-relaxin gene family known to be expressed in the ovarian follicular thecal cells of ruminants. To investigate the pattern of RLF expression in development and atresia of bovine follicles, antisera were raised in rats and rabbits to recombinantly expressed bovine pro-RLF and to chemically synthesized ovine RLF B chain, respectively. On dot blotting analysis, the rat antiserum bound to pro-RLF and less strongly to a synthetic mature ovine RLF lacking the C-domain, whereas the rabbit antiserum bound the mature form of ovine RLF. These antisera were used to immunostain bovine ovarian follicles of differing sizes and stages of health and atresia. 3beta-Hydroxysteroid dehydrogenase was colocalized with pro-RLF (n = 86 follicles), and cholesterol side-chain cleavage cytochrome P450 was localized in another section of many of the same follicles (n = 66). Not all follicles expressed pro-RLF in the theca interna, so the results are presented as the proportion of follicles expressing pro-RLF. Both mature and pro-RLF were immunolocalized to steroidogenic thecal cells of healthy follicles. As follicles enlarged to >5 mm, the proportion expressing pro-RLF declined (19/19 for <5 mm and 18/26 for >6 mm). Atresia was divided into antral (antral granulosa cells dying first) or basal (basal cells dying first) and further divided into early, middle, and late. For antral atresia of small follicles (2-5 mm), no decline in the proportion expressing pro-RLF was observed (early 6/6, middle 2/2) until the late stages (1/4). For basal atresia, which only occurs in small follicles (2-5 mm), the proportion expressing pro-RLF declined in the middle (2/5) and late (0/8) stages. In larger follicles (>6 to <10 mm), the proportion expressing pro-RLF also declined with atresia (1/13). These declines in RLF expression with atresia or increasing size were not accompanied by a decline in the expression of steroidogenic enzymes in the theca interna. A significant (P < 0.001) inverse relationship in the expression of pro-RLF and 3beta-hydroxysteroid dehydrogenase in the membrana granulosa was observed. We conclude that the expression of pro-RLF in the theca interna is switched off as follicles enlarge or enter atresia, whereas the expression of steroidogenic enzymes is maintained in the theca interna.

3-Hydroxysteroid Dehydrogenases↗
PubMed1990

A common ancestor for human placental 17 beta-hydroxysteroid dehydrogenase, Streptomyces coelicolor actIII protein, and Drosophila melanogaster alcohol dehydrogenase.

A computer-based comparison of the amino acid sequences of human placental 17 beta-hydroxysteroid dehydrogenase and Streptomyces coelicolor actIII protein, which is important in the synthesis of the antibiotic actinorhodin, gives an alignment score 12.15 standard deviations higher than that of 1000 comparisons of randomized sequences of these proteins. The probability of getting this score by chance is 3 x 10(-34). Comparison of actIII protein with Drosophila melanogaster alcohol dehydrogenase yields a score of 10.3 standard deviations (P = 3.5 x 10(-25)). Based on these similarities, we propose that 17 beta-hydroxysteroid dehydrogenase, actIII protein, and Drosophila alcohol dehydrogenase are derived from a common ancestor.

17-Hydroxysteroid Dehydrogenases↗
PubMed2003

Estrogen receptors (alpha and beta) and 17beta-hydroxysteroid dehydrogenase type 1 and 2 in thyroid disorders: possible in situ estrogen synthesis and actions.

Both epidemiological and experimental findings suggest the possible roles of sex steroids in the pathogenesis and/or development of various human thyroid disorders. In this study, we evaluated the expression of estrogen receptors (ER) alpha and beta in normal thyroid glands (N = 25; female: n = 13, male: n = 10, unknown: n = 2) ranging in age from fetus to adult. Furthermore, using immunohistochemistry, we investigated the expression of ERalpha and beta in 206 cases of thyroid disorders, including 24 adenomatous goiters, 23 follicular adenomas, and 159 thyroid carcinomas. In addition, we also studied the mRNA expression of ERalpha and beta and 17beta-hydroxysteroid dehydrogenase Type 1 and 2, enzymes involved in the interconversion between estrone and estradiol, using reverse transcription polymerase chain reaction (RT-PCR), in 48 of these 206 cases (10 adenomatous goiters, 10 follicular adenomas, and 28 papillary thyroid carcinomas) in which fresh frozen tissues were available for examination to further elucidate the possible involvement of intracrine estrogen metabolism and/or actions in thyroid disorders. ERalpha labeling index, or percentage of cells immunopositive for ERalpha, was significantly higher in adenomatous goiter (14.2 +/- 6.4), follicular adenoma (13.4 +/- 5.1), and thyroid carcinoma (16.4 +/- 2.1) than in normal thyroid gland (0; P <.05). Few follicular cells were positive for ERalpha in normal thyroid glands. In papillary carcinoma, ERalpha labeling index was significantly higher in premenopausal women (28.1 +/- 4.5) than in postmenopausal women (14.2 +/- 2.9) and in men of various ages (7.6 +/- 2.7; P <.05). In other histological types of thyroid carcinoma, no significant correlations were detected. ERbeta immunoreactivity was detected in both follicular and C-cells of normal thyroid glands, including those in developing fetal thyroid glands. In addition, ERbeta immunoreactivity was detected in the nuclei of various thyroid lesions. But no significant correlations were detected between ERbeta labeling index and clinicopathological findings including age, menopausal status, gender, and/or histological type of thyroid lesions. 17beta-hydroxysteroid dehydrogenase Type 1 expression was detected in 31/48 (64.0%) of the cases examined, whereas Type 2 was detected only in 3/46 (6.3%) of all the cases examined. These results demonstrated that estrogens may influence the development, physiology, and pathology of human thyroid glands, and these effects, especially through ERalpha, may become more pronounced in neoplasms, particularly in papillary carcinoma arising in premenopausal women.

Adenocarcinoma↗
PubMed2001

Crystallization and preliminary X-ray crystallographic analysis of the human type 3 3 alpha-hydroxysteroid dehydrogenase at 1.8 A resolution.

In androgen-sensitive target tissues, 3 alpha-hydroxysteroid dehydrogenase regulates the androgen receptor (AR) activity by catalyzing the inactivation of 5 alpha-dihydrotestosterone (the most natural potent androgen) to 5 alpha-androstane-3 alpha,17 beta-diol. In this report, the crystallization of a human prostatic type 3 3 alpha-hydroxysteroid dehydrogenase, a member of the aldo-keto reductase superfamily, is described. Two different crystal forms of the complex between the human type 3 3 alpha-HSD, NADP(+) and testosterone have been obtained using PEG as precipitant. Crystal form I, which diffracts to 1.6 A, belongs to the monoclinic space group P2(1), with unit-cell parameters a = 55.07, b = 87.15, c = 76.88 A, beta = 107.37 degrees and two subunits in the asymmetric unit. A complete data set has been collected at 1.8 A. Crystal form II, which diffracts to 2.6 A, belongs to the rhombohedral space group R32, with unit-cell parameters a = b = 143.59, c = 205.86 A, alpha = beta = 90, gamma = 120 degrees and two subunits in the asymmetric unit.

3-Hydroxysteroid Dehydrogenases↗
PubMed2002

Purification, crystallization and preliminary X-ray diffraction results of human 17beta-hydroxysteroid dehydrogenase type 5.

17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) catalyze the last step in the biosynthesis of all androgens and estrogens, thus playing a pivotal role in sex-hormone metabolism. Human 17beta-HSD type 5 (17beta-HSD5) catalyzes hydride transfer at the 17beta-hydroxy position, but possesses high sequence homology to 3alpha-hydroxysteroid dehydrogenases (3alpha-HSD). Two crystal forms of 17beta-HSD5 in an enzyme-testosterone-NADP ternary complex have been obtained under different crystallization conditions. A form I crystal obtained at pH 8.5 diffracted to 1.32 A. It belonged to space group P2(1), with unit-cell parameters a = 47.41, b = 77.16, c = 48.67 A, beta = 116.32 degrees. Form II crystals obtained at pH 6.5 diffracted to 2.0 A and belonged to space group P6(3), with unit-cell parameters a = b = 110.58, c = 56.89 A.

17-Hydroxysteroid Dehydrogenases↗
PubMed2005

Crystallization, X-ray diffraction analysis and phasing of 17beta-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus.

17beta-Hydroxysteroid dehydrogenase from the filamentous fungus Cochliobolus lunatus (17beta-HSDcl) is an NADP(H)-dependent enzyme that preferentially catalyses the oxidoreduction of oestrogens and androgens. The enzyme belongs to the short-chain dehydrogenase/reductase superfamily and is the only fungal hydroxysteroid dehydrogenase known to date. 17beta-HSDcl has recently been characterized and cloned and has been the subject of several functional studies. Although several hypotheses on the physiological role of 17beta-HSDcl in fungal metabolism have been formulated, its function is still unclear. An X-ray crystallographic study has been undertaken and the optimal conditions for crystallization of 17beta-HSDcl (apo form) were established, resulting in well shaped crystals that diffracted to 1.7 A resolution. The space group was identified as I4(1)22, with unit-cell parameters a = b = 67.14, c = 266.77 A. Phasing was successfully performed by Patterson search techniques. A catalytic inactive mutant Tyr167Phe was also engineered, expressed, purified and crystallized for functional and structural studies.

17-Hydroxysteroid Dehydrogenases↗
PubMed1988

delta 5-3 beta-hydroxysteroid dehydrogenase activity in sebaceous glands of scalp in male-pattern baldness.

Sebaceous glands were isolated by manual dissection using a stereomicroscope from skin specimens of bald scalp of men with male-pattern baldness undergoing hair transplant or scalp reduction surgery and also from specimens taken from hairy and bald areas of scalp at autopsy of adult male victims of accidental death within 3 h post mortem. Homogenates of the isolated glands exhibited activities of delta 5-3 beta-hydroxysteroid dehydrogenase (3 beta HSD), 17 beta-hydroxysteroid dehydrogenase, and testosterone 5 alpha-reductase by the conversion of [3H]dehydroepiandrosterone (DHA) to 3H-delta 4-androstenedione (AD), [3H]testosterone, and [3H]dihydrotestosterone. Homogenates of glands from bald (B) scalp had greater 3 beta HSD activity than homogenates of glands from hairy (H) scalp. After differential centrifugation, 3 beta HSD activity was found mainly in the microsomal and 105,000 X g supernatant fractions. Specific activity of the enzyme based on protein mass was highest in the microsomal fraction; however, the total 3 beta HSD activity in the 105,000 X g supernatent of B glands was significantly (p less than .01) greater than that of H glands. 3 beta HSD activity in sebaceous glands isolated from autopsy specimens did not differ from that of glands isolated from surgical specimens in apparent Km (0.13-0.14 microM), pH optima (8.0), or coenzyme requirement for NAD. Since substantial 3 beta HSD activity was present in the cytosol, and cytosol of B glands showed increased 3 beta HSD activity, the increased conversion of DHA to AD may be a critical step for androgenic action and may be responsible for excessive androgenicity in male-pattern baldness.

3-Hydroxysteroid Dehydrogenases↗
PubMed1984

A cytochemical section bioassay for plasma trilostane: an orally active inhibitor of 3 beta-hydroxysteroid dehydrogenase activity.

Trilostane is a competitive inhibitor of 3 beta-hydroxysteroid dehydrogenase activity in vitro and an orally active inhibitor of steroidogenesis in vivo. A cytochemical section bioassay for this drug (4 alpha, 5-epoxy-17 beta-hydroxy-3-oxo-5 alpha-androstane-2 alpha-carbonitrile) in human plasma has been developed. The assay is based upon the inhibition of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity in the corpus luteum of unfixed tissue sections (6 micron) of the mature dioestrous rat ovary. Trilostane is extracted from plasma by a simple chloroform procedure. The standard curve (0.15-2.5 mumol/l pure trilostane) exhibits a four-fold change in 3 beta-HSD activity and is constructed in the presence of extract from control plasma pools. The detection limit of the plasma assay is 2 mumol/l trilostane after allowing for dilution effects and recovery losses. This level gives a significantly different response from the zero quality control (P less than 0.05) and has an inter-assay coefficient of variation of less than 15%. No false positives have been recorded to date and the majority of samples from subjects receiving therapeutic doses of the drug have levels of greater than 2 mumol/l. Intra- and inter-assay coefficients of variation using both plasma quality controls and unknown samples are 4% (n = 15) and 13.9% (n = 27) respectively. Recovery is 80 +/- 9% (n = 13) and 79 +/- 10% (n = 10) for plasma quality controls containing 12 and 4.8 mumol/l trilostane respectively. Dilutions (up to 1:5) of plasma extracts are parallel to the standard curve and the assay throughput is approximately 16 samples/week technician.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxysteroid Dehydrogenases↗
PubMed1985

Familial male pseudohermaphroditism with gynaecomastia due to 17 beta-hydroxysteroid dehydrogenase deficiency. A report of 3 cases.

Three sisters with male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency are described. On the basis of a 46 XY karyotype and female phenotype all subjects were thought to have the testicular feminization syndrome. At puberty the two older patients developed signs of virilization and gynaecomastia. In these patients the plasma androstenedione level was 4-5 times higher than normal, whilst the plasma testosterone level was low compared to the normal range and, under basal conditions, their plasma androstenedione to testosterone ratio was 20-25 times higher than normal. Interestingly, in the third, prepubertal case, the basal androstenedione to testosterone ratio was normal but became six times higher than normal after hCG stimulation. These data support the diagnosis of male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency and underline the diagnostic value of the hCG stimulation test prepubertally.

17-Hydroxysteroid Dehydrogenases↗
PubMed1996

Molecular cloning of mouse 17 beta-hydroxysteroid dehydrogenase type 1 and characterization of enzyme activity.

The biological activity of certain estrogens and androgens is modulated by enzymes called 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs), which catalyze the interconversion between less active 17-oxosteroid and more active 17 beta-hydroxysteroid forms. In the present report, we describe cloning of mouse 17 beta-HSD type-1 cDNA from an ovarian library generated from 4,4'-(1,2-diethyl-1,2-ethenediyl)bisphenol-(diethylstilbestrol)-tr eated mice, and characterization of the corresponding enzyme. The open reading frame of the mouse 17 beta-HSD type-1 cDNA encodes a peptide of 344 amino acid residues with a predicted molecular mass of 36785 Da. The mouse 17 beta-HSD type-1 enzyme shares 63% and 93% overall identity with human and rat 17 beta-HSD type-1 enzymes, respectively, and the most striking differences between the mouse and human type-1 enzymes are between the amino acid residues 197 and 230 and in the carboxy terminus of the enzymes. Similarly to the human 17 beta-HSD type-1 enzyme, the mouse type-1 enzyme primarily catalyzes reductive reactions from 17-oxo forms to 17 beta-hydroxy forms in intact cultured cells, but unlike the human type-1 enzyme, the mouse enzyme does not prefer phenolic over neutral substrates. Thus, mouse 17 beta-HSD type 1 catalyzes reduction of androst-4-ene-3,17-dione (androstenedione) to 17 beta-hydroxyandrost-4-en-3-one (testosterone) as efficiently as 3 beta-hydroxyestra-1,3,5(10)-trien-17-one (estrone) to estra-1,3,5(10)-triene-3 beta, 17 beta-diol (estradiol). 17 beta-HSD type 1 is predominantly expressed in mouse ovaries, in which it is located in granulosa cells.

17-Hydroxysteroid Dehydrogenases↗
PubMedDate not supplied

In vitro studies on histochemical localization of testicular delta5-3beta-hydroxysteroid dehydrogenase activity from indomethacin pretreated rats--effect of prostaglandins and luteinizing hormone.

In vitro studies on the effect of LH and prostaglandins on delta5 3beta-hydroxysteroid dehydrogenase activity using indomethacin pre-treated testis as the experimental model, revealed a greater stimulation of the enzyme activity when the incubation medium contained LH and PGE2 both at a concentration of 1 microgram/ml in comparison to the effect produced by 1 microgram LH/ml alone, but the augmentory effect of PGE2 on testicular response to LH was not evidenced as the LH: PGE2 ratio became 1 : 10. Neither PGE2 nor PGF2A produced any stimulation of the enzyme activity at concentrations of 1, 10, or 20 microgram/ml in the incubating medium. PGF2A at concentrations of 1 or 10 microgram/ml did not appear to interfere with LH action on this steroidogenic enzyme. On the contrary, prostaglandins, both PGE2 and PGF2A, at concentrations of 20 microgram/ml, antagonized LH action over testicular delta5-3beta-hydroxysteroid dehydrogenase activity. On the basis of these findings, it appears that prostaglandin E2 in some way, is necessary for manifestation of the steroidogenic action of LH in testis.

3-Hydroxysteroid Dehydrogenases↗
PubMed1975

Enzymatic transformation of morphine by hydroxysteroid dehydrogenase from Pseudomonas testosteroni.

Eznyme preparations from Pseudomonas testosteroni containing alpha- and beta- hydroxysteroid dehydrogenases catalyzed the oxidation of morphine and codeine by nicotinamide adenine dinucleotide. Morphine was converted in relatively low yield into 14-hydroxymorphinone probably via morphinone as an intermediate. Codeine was converted to codeinone and 14-hydroxycodeinone. Only the conversions at the 6-position were carred out by the hydroxysteroid dehydrogenase. Hydroxylation at the 14-position did occur spontaneously (or enzymatically with a contaminating enzyme) ater oxidation at the 6-position.

Androsterone↗
PubMed1979

3 beta-hydroxysteroid dehydrogenase deficiency. Follow-up study in a girl with pubertal bone age.

Follow-up data on a girl with 3 beta-hydroxysteroid dehydrogenase deficiency at a pubertal bone age are presented. On examination at age 14.7 years (bone age 12 years), there was no spontaneous breast development. On treatment with hydrocortisone and fludrocortisone, most steroids with the exception of increased 17OH-pregnenolone in plasma and delta 5-pregnenetriol and pregnanetriol in urine, were normal. After 1 week off hydrocortisone, plasma 17OH-pregnenolone, DHA and delta5-androstenediol and urinary delta 5-pregnenetriol and pregnanetriol increased markedly, while plasma 17OH-progesterone increased only slightly. On increased hydrocortisone medication, there was no response of plasma estradiol to HMG. This first observation of a pubertal girl with 3 beta-hydroxysteroid dehydrogenase deficiency indicates that in this patient, the defect persists at a pubertal bone age and that it is not limited to the adrenals, but also affects the ovaries. Girls with this type of defect thus require estrogen replacement at a bone age of about 12 years. The large quantities of pregnanetriol in the urine are not due to an incomplete defect or an additional 21-hydroxylase deficiency, but most likely to the peripheral or hepatic conversion of 17OH-pregnenolone or delta 5-pregnenetriol.

3-Hydroxysteroid Dehydrogenases↗
PubMed1985

Estradiol acts as a competitive inhibitor of the 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase enzyme of cultured Leydig tumor cells.

To study the local regulatory mechanisms involving steroid hormones in steroidogenic cells, the effect of estradiol on steroidogenesis was investigated using MA-10 Leydig tumor cells. Estradiol inhibited progesterone biosynthesis in MA-10 cells in a dose-dependent manner. Inhibition of progesterone biosynthesis by estradiol was associated with a concomitant accumulation of pregnenolone in the incubation medium. Estradiol inhibited the activity of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase by a chemical mechanism which is not mediated through the cellular estrogen receptor. Thus, the estrogen receptor agonist diethylstilbestrol did not inhibit this enzyme activity, nor could this agent block the effect of estradiol on the enzyme. Furthermore, estradiol inhibited enzyme activity in isolated microsomes which do not contain estradiol receptor protein. Kinetic analysis of the inhibitory effect of estradiol on 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase revealed that this steroid hormone functions as a competitive inhibitor of the enzyme, with an average apparent Ki of 1.8 microM.

3-Hydroxysteroid Dehydrogenases↗