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PubMed1990

Human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase from placenta: expression in nonsteroidogenic cells of a protein that catalyzes the dehydrogenation/isomerization of C21 and C19 steroids.

The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. The insert contains an open reading frame encoding a protein of 372 amino acids, the initial 29 amino acids corresponding to the N-terminal sequence identified from the purified human placental microsomal enzyme. The cDNA was inserted into a modified pCMV vector and expressed in COS-1 monkey kidney tumor cells. The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. Transfected COS cell homogenates, supplemented with NAD+, very efficiently oxidized 5 alpha-androstan-3 beta,17 beta-diol to 5 alpha-dihydrotestosterone and, upon addition of NADH, reduced 5 alpha-dihydrotestosterone to 5 alpha-androstan-3 beta,17 beta-diol. Thus, the dehydrogenation/isomerization steps of steroid biosynthesis can be catalyzed by a single polypeptide chain, which can metabolize all of the major physiological substrates.

17-alpha-Hydroxypregnenolone↗
PubMed1990

Regulation of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase expression and activity in the hypophysectomized rat ovary: interactions between the stimulatory effect of human chorionic gonadotropin and the luteolytic effect of prolactin.

The enzyme 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) catalyzes an obligatory step in the conversion of pregnenolone and other 5-ene-3 beta-hydroxysteroids into progesterone as well as precursors of all androgens and estrogens in the ovary. Since 3 beta-HSD is likely to be an important target for regulation by pituitary hormones, we have studied the effect of chronic treatment with LH (hCG), FSH, and PRL on ovarian 3 beta-HSD expression and activity in hypophysectomized adult female rats. Human CG (hCG) [10 IU, twice a day (bid)], ovine FSH (0.5 microgram, bid), and ovine PRL (1 mg, bid) were administered, singly or in combination, for a period of 10 days starting 15 days after hypophysectomy. In hypophysectomized rats, PRL exerted a potent inhibitory effect on all the parameters studied. In fact, PRL caused a 81% decrease in ovarian 3 beta-HSD mRNA content accompanied by a similar decrease in 3 beta-HSD activity and protein levels. In addition, ovarian weight decreased by 40% whereas serum progesterone fell dramatically from 1.92 nmol/liter to undetectable levels after treatment with PRL. Whereas hCG alone had only slight stimulatory effects on 3 beta-HSD mRNA, protein content and activity levels, treatment with the gonadotropin partially or completely reversed the potent inhibitory effects of oPRL on all the parameters measured. FSH, on the other hand, had no significant effect on 3 beta-HSD expression and activity. In situ hybridization experiments using the 35S-labeled rat ovary 3 beta-HSD cDNA probe show that the inhibitory effect of PRL is exerted primarily on luteal cell 3 beta-HSD expression and activity. On the other hand, it can be seen that hCG stimulates 3 beta-HSD mRNA accumulation in interstitial cells. The present data show that hCG and PRL exert potent and opposite cell-specific effects on ovarian 3 beta-HSD expression, activity, and content in the rat ovary. Moreover, the present study could suggest that female infertility associated with hyperprolactinemia in women could well be related, at least in part, to the potent inhibitory effect of PRL on ovarian 3 beta-HSD expression and activity.

3-Hydroxysteroid Dehydrogenases↗
PubMed1991

Prostaglandin E2 is a positive regulator of adrenocorticotropin receptors, 3 beta-hydroxysteroid dehydrogenase, and 17 alpha-hydroxylase expression in bovine adrenocortical cells.

The maintenance of optimal steroidogenesis in adrenocortical cells primarily depends on the chronic action of cAMP. Herein we examine the effects of prostaglandin E2 (PGE2) on the differentiated functions of bovine adrenocortical (BAC) cells in primary culture. PGE2 (10 microM) treatment for 3 h stimulated steroidogenesis and cAMP production by over 100-fold. In addition, the cAMP antagonist Rp-cAMP (1 mM) inhibited PGE2 stimulation of steroidogenesis by 60%. This observation suggests that the cAMP second messenger system is responsible for much of the PGE2-activated steroid hormone synthesis. Chronic treatment of BAC cells with PGE2 caused induction of 3 beta-hydroxysteroid dehydrogenase and steroid 17 alpha-hydroxylase cytochrome P-450 expression as determined by the examination of enzyme activity, enzyme levels by immunoblotting, and specific messenger RNA (mRNA) levels by Northern analysis. The positive effects of PGE2 on expression of 3 beta-hydroxysteroid dehydrogenase and 17 alpha-hydroxylase cytochrome P-450 were similar to the effects seen after ACTH treatment of BAC cells. In addition, treatment of BAC cells with PGE2 for 3 days caused a 3-fold induction of ACTH receptors as determined by increased cell binding of [125I]ACTH. Finally, we determined that BAC cells produced PGE2 and that the level of synthesis increased 10-fold after treatment with the hormone angiotensin II. Taken together these data indicate that PGE2 is a positive regulator of BAC cell differentiation acting on ACTH receptors, steroid metabolizing enzymes, and steroidogenesis. The ability of BAC cells to produce PGE2 leaves open the possibility for paracrine and autocrine regulation within the adrenal.

3-Hydroxysteroid Dehydrogenases↗
PubMed1996

Cloning of rat 17 beta-hydroxysteroid dehydrogenase type 2 and characterization of tissue distribution and catalytic activity of rat type 1 and type 2 enzymes.

17 beta-Hydroxysteroid dehydrogenases (17HSDs) are enzymes catalyzing the conversion between 17 beta-hydroxy- and 17-ketosteroids. Both estrogens and androgens possess their highest activity in the 17 beta-hydroxy form, and the enzymes, therefore, regulate the biological activity of sex hormones. In this study, we have characterized the complementary DNA (cDNA) for rat 17HSD type 2. The cDNA encodes a protein with a predicted mol wt of 42,010 Da. The protein has 77% similarity and 62% identity with the human 17HSD type 2 enzyme. Furthermore, the hydropathicity profiles of the enzymes are very similar. The two isozymes contain a putative transmembrane region close to the N-terminus. However, the rat isozyme lacks the two lysine-rich amino acid cluster present at the N- and C-terminals of human 17HSD type 2. The tissue distribution of the rat 17HSD type 1 and type 2 enzymes is very similar to that of the human enzymes. The highest expression of 17HSD type 2 was detected in the placenta. In addition, a 1.5-kilobase messenger RNA for the enzyme was detected in the small intestine, liver, and kidney of both sexes. The two messenger RNAs for rat 17HSD type 1 (1.4 and 1.7 kilobases) were highly expressed only in the ovary, and at very low concentrations in the kidney of both sexes. Transiently expressed rat 17HSD type 2 showed oxidative activity almost exclusively in cultured human embryonic kidney 293 cells, converting estradiol into estrone and testosterone into androstenedione, whereas the opposite was observed for the rat type 1 enzyme. The data suggest that similarly to the corresponding human isoforms, rat 17HSD type 2 is mostly involved in the oxidation of 17 beta-hydroxysteroids into their relatively inactive keto derivative in peripheral tissues, whereas rat 17HSD type 1 is mainly involved in the glandular biosynthesis of estradiol.

17-Hydroxysteroid Dehydrogenases↗
PubMed1976

Deficient 17 beta-hydroxysteroid oxidoreductase activity in testes from a male pseudohermaphrodite.

17beta-Hydroxysteroid oxidoreductase (17 beta-HOR) activity in testicular tissue from a male pseudohermaphrodite (MP) who had elevated plasma LH and androstenedione (A) levels, and normal dehydroepiandrosterone (DHA) levels was compared by in vitro studies to that of testicular tissue from a normal man. The 17 beta-HOR activity from the MP was localized predominantly in the microsomal fraction, as it is in normal testicular tissue. With DHA, A, and estrone as substrates, the 17 beta-HOR activity of the MP was decreased in the presence of NADPH, but not NADH, in comparison with the normal. NADPH was the preferred co-factor for 17 beta-HOR from the normal testes, while 17 beta-HOR activity from the MP testes was less with NADPH than with NADH as cofactor. These results indicate that the inefficient testosterone production in the MP testes may be accounted for by a deficiency of NADPH-dependent 17 beta-HOR activity. Further studies suggested that 3 beta-hydroxysteroid oxidoreductase-isomerase (3 beta-HOR) was increased in the MP testes and was much greater than 17 beta-HOR activity with DHA as substrate. These findings largely explain the elevated plasma A levels with normal DHA levels, and suggest that DHA leads to A leads to testosterone was the major route of testosterone biosynthesis in the MP testes.

Androstenedione↗
PubMed1977

Studies of the human testis. VIII. Product activation of 17beta-hydroxysteroid oxidoreductase for testosterone.

Cell-free homogenates prepared from human testis tissue were incubated with either 1.3 x 10(-5)M[4-14C]testosterone and 2 x 10(-4)M NADP or 1.3 x 10(-5) [4-14C]nadrostenedione and 2 x 10(-4)M NADPH. Addition of non-radioactive androstenedione and testosterone to the incubation medium increased the formation of [14C]androstenedione from [4-14C]testosterone and [14C]testosterone from [4-14C]androstenedione, respectively, while addition of product nucleotide NADPH or NADP, respectively, decreased the conversions. The addition of androstenedione to the incubation medium changed the apparent optimal pH of 17beta-hydroxysteroid oxidoreductase for testosterone from 8.6 to 8.0. It appears likely that in a cell-free system human testicular 17beta-hydroxysteroid oxidoreductase not solubilized and still attached to membrane is activated by the product of the reaction catalyzed by the enzyme.

17-Hydroxysteroid Dehydrogenases↗
PubMed1983

Human ovarian 17 beta-hydroxysteroid oxidoreductase activity: a comparison of normal and polycystic ovarian tissues.

Ovarian tissue and ovarian venous blood were obtained from women undergoing wedge resection, and ovarian tissue was obtained from normally menstruating women who had an oophorectomy for medical reasons. A morphological evaluation was made of the wedged tissue. 17 beta-Hydroxysteroid oxidoreductase levels were determined as the 17-ketoreductase (17-KR) and 17 beta-dehydrogenase activities in both normal and wedged tissue. Plasma androstenedione (A) and testosterone (T) levels were measured in the ovarian venous blood. Low, but measurable, 17 beta-hydroxysteroid oxidoreductase activity was found in the mitochondria, microsomes, and cytosol. With whole, cell-free homogenates, mean 17-KR activity was not significantly different in normal tissues and polycystic tissues; mean 17-KR activity of corpora lutea was significantly greater than that of the other tissues. Mean 17 beta-dehydrogenase activity was not significantly different from 17-KR activity in the tissues studied. Ovarian venous A levels were higher than the reported mean ovarian venous A levels of normal women with only one exception; approximately half of the ovarian venous T levels were higher than reported mean ovarian venous T levels of normal women. The morphology of the wedge sections did not correlate well with the biochemical data.

17-Hydroxysteroid Dehydrogenases↗
PubMed1985

Late-onset adrenal steroid 3 beta-hydroxysteroid dehydrogenase deficiency. I. A cause of hirsutism in pubertal and postpubertal women.

To investigate the adrenal cause of hyperandrogenism in peri- and postpubertal hirsute women, baseline and ACTH-stimulated serum concentrations of delta 5-17-hydroxypregnenolone (delta 5-17P), dehydroepiandrosterone (DHEA) and its sulfate, 17-hydroxyprogesterone (17-OHP), cortisol, delta 4-androstenedione, and testosterone were determined in 116 women with hirsutism or acne of peri- and postpubertal onset with or without menstrual abnormalities. The results were compared with the same steroid concentrations in 30 normal age-matched women. Sixteen of the 116 women with hirsutism whose ACTH-stimulated 17-OHP levels (mean +/- SD, 5404 +/- 3234 ng/dl; normal, 334 +/- 194) were markedly elevated while their ratios of delta 5-17P to 17-OHP (0.4 +/- 0.2; normal, 3.4 +/- 1.5) were low were diagnosed as having nonclassical symptomatic 21-hydroxylase deficiency. Seventeen other hirsute women, including 3 siblings, had very high responses of delta 5-17P (2276 +/- 669 ng/dl; normal, 985 +/- 327) and DHEA (2787 +/- 386 ng/dl; normal, 1050 +/- 384) to ACTH stimulation, with significantly elevated ratios of delta 5-17P to 17-OHP (11 +/- 2.0; normal, 3.4 +/- 1.5) and DHEA to delta 4-androstenedione (7.5 +/- 2.3; normal, 4.6 +/- 1.5). In these hirsute women, the morning serum delta 5-17P and DHEA concentrations were elevated, had a diurnal variation, and were suppressed with dexamethasone administration. We propose that partial adrenal 3 beta-hydroxysteroid dehydrogenase deficiency is the cause of hirsutism in these women. This may represent an allelic variant at the genetic locus for 3 beta-hydroxysteroid dehydrogenase deficiency similar to that reported for symptomatic nonclassical 21-hydroxylase deficiency producing peripubertal excess androgen syndrome.

3-Hydroxysteroid Dehydrogenases↗
PubMed1985

Kinetic analysis of adrenal 3 beta-hydroxysteroid dehydrogenase activity during human development.

Kinetic analyses of microsomal 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity in adrenal glands from 11 individuals, aged 1-60 yr, were carried out to determine whether changes in substrate or cofactor affinity (Km) or cellular content, as reflected in maximal velocity, could explain the changes in adrenal delta 5-3 beta-hydroxysteroid secretion that occur in late childhood and puberty. The Km values for the cofactor NAD+ were similar regardless which substrate, dehydroepiandrosterone (DHA), pregnenolone, or 17-hydroxypregnenolone (17OH-delta 5P), was used. The Km values for DHA (0.3 microM), pregnenolone (0.4 microM), and 17OH-delta 5P (0.3 microM) were similar and within the intraadrenal concentration ranges for DHA and 17OH-delta 5P previously reported. Each substrate was a competitive inhibitor for the others, with close similarity between affinity and inhibition constants. These observations point to the presence of a single 3 beta-HSD, rather than several substrate-specific variants. There was no change in substrate Km with age; the maximal velocity was lower (0.1-0.6 nmol/mg X min) in a single 1-yr-old infant than in later life, but there was no significant change (mean, 2.9-4.6 nmol/mg X min for the three substrates) between values at 12 and 60 yr. This suggests that ACTH-mediated induction of 3 beta-HSD may be low in infancy and higher in adults, while in vivo studies point to a reduction in actual 3 beta-HSD activity during this period. The likely explanation for this paradox between enzyme levels and final activity is that 3 beta-HSD is progressively inhibited during late childhood and puberty by rising intraadrenal concentrations of various delta 4-3-ketosteroids.

17-alpha-Hydroxypregnenolone↗
PubMed1986

Steroid inhibitory effects upon human adrenal 3 beta-hydroxysteroid dehydrogenase activity.

The inhibitory effects of varying concentrations of steroids upon 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) kinetics were studied in human adrenal microsomes. Each enzyme assay was conducted in triplicate at five different concentrations of three substrates (dehydroepiandrosterone, pregnenolone, and 17OH-pregnenolone), using microsomes from at least three donors. Each steroid was screened for possible inhibition at concentrations of 10(-8) and 10(-6) M and then studied in more detail at five different concentrations. The type of inhibition and the inhibition constant (Ki) were determined by analysis of Lineweaver-Burk and Dixon plots, together with replots of the slopes from the Dixon plots. The mean Km (Michaelis-Menten constant) for the three substrates was 0.42 +/- 0.04 (SE) mumol/liter (n = 73). Each steroid tested, including delta 5-3 beta-hydroxysteroids, estrogens, and several delta 4-3-ketosteroids, with the exception of cortisol, caused significant inhibition of 3 beta-HSD activity, and in each case the steroid appeared to behave as a competitive inhibitor. In most cases the Ki value was approximately 10(-7) M. At micromolar concentrations several steroids, notably estrone and estradiol, caused almost total inhibition of adrenal 3 beta-HSD activity. Comparison of the calculated Ki values with available data concerning changes in intra-adrenal steroid concentrations during childhood suggests that these changes would be sufficient to cause a relative decline in 3 beta-HSD activity during adrenarche. Although postnatal circulating steroid concentrations would appear to be insufficient to influence adrenal steroidogenesis, the high serum levels of placental steroids during fetal life would be expected to cause marked 3 beta-HSD inhibition.

3-Hydroxysteroid Dehydrogenases↗
PubMed1994

No evidence of mutations in the genes for type I and type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) in nonclassical 3 beta HSD deficiency.

Nonclassical 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase deficiency (NC3 beta HSDD) has been diagnosed in hyperandrogenic women with an increasing frequency during the last 14 yr. Fifteen menarcheal women with androgen excess syndrome, diagnosed with NC3 beta HSDD previously were restudied, in 12 after discontinuation of glucocorticoid treatment, in 2 patients never treated with glucocorticoids, and in 1 both before and after glucocorticoid therapy. Each of the 15 patients underwent ACTH stimulation testing, in some cases on multiple occasions. Although some (very few) patients seem to have improved with time, others remained the same or got worse. Molecular DNA analysis was also performed in 6 of the patients, using the strategy successfully used to detect point mutations in the type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) gene, which are responsible for classical 3 beta HSD deficiency. This strategy consists of the direct sequencing of polymerase chain reaction-amplified DNA fragments corresponding to the complete coding sequence and all intron-exon junctions and to the 5'- and 3'-noncoding region of this gene. We were unable to demonstrate any mutation of the type II 3 beta HSD gene in these 6 patients. To gain additional information about potential mutations, direct sequencing of the type I 3 beta HSD gene was also performed using this same strategy, and no mutations were found. The present study strongly suggests that unlike the salt-losing and nonsalt-losing forms of classical 3 beta HSD deficiency, NC3 beta HSDD is not due to a mutant type II 3 beta HSD enzyme. However, the possibility remains of a mutation(s) in the unsequenced regions of the type II 3 beta HSD gene or elsewhere, such as in a gene for modulatory protein, playing a specific role in the expression of the type II 3 beta HSD gene. On the other hand, knowing the multiple hormonal controls to which 3 beta HSD activity is subject, it cannot be excluded that at least in some cases, NC3 beta HSDD may be an acquired defect, the result of endogenous or environmental factors.

3-Hydroxysteroid Dehydrogenases↗
PubMed1996

Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency.

Autosomal recessive mutations in the 17 beta-hydroxysteroid dehydrogenase 3 gene impair the formation of testosterone in the fetal testis and give rise to genetic males with female external genitalia. Such individuals are usually raised as females, but virilize at the time of expected puberty as the result of increases in serum testosterone. Here we describe mutations in 12 additional subjects/families with this disorder. The 14 mutations characterized to date include 10 missense mutations, 3 splice junction abnormalities, and 1 small deletion that results in a frame shift. Three of these mutations have occurred in more than 1 family. Complementary DNAs incorporating 9 of the 10 missense mutations have been constructed and expressed in reporter cells; 8 of the 9 missense mutations cause almost complete loss of enzymatic activity. In 2 subjects with loss of function, missense mutations testosterone levels in testicular venous blood were very low. Considered together, these findings strongly suggest that the common mechanism for testosterone formation in postpubertal subjects with this disorder is the conversion of circulating androstenedione to testosterone by one or more of the unaffected 17 beta-hydroxysteroid dehydrogenase isoenzymes.

17-Hydroxysteroid Dehydrogenases↗
PubMed1991

Regulation of expression of male-specific rat liver microsomal 3 beta-hydroxysteroid dehydrogenase.

In the steroidogenic pathways present in the gonads and adrenal cortex, 3 beta-hydroxysteroid dehydrogenase isomerase (3 beta HSD) is a key enzyme which controls the formation of delta 4-3-ketosteroids from delta 5-3 beta-hydroxysteroids. Herein, we used an antibody against human placental 3 beta HSD and a rat testicular 3 beta HSD cDNA probe to study the expression of rat liver 3 beta HSD mRNA and protein. Rat liver microsomal 3 beta HSD activity has been previously reported to exhibit a significant sex difference, with much higher activity in the male. We have shown an age-dependent increase in levels of immunoreactive 3 beta HSD through the time of maturation of the male rat. The immunoreactive protein, of similar molecular size to the human placental and rat testicular 3 beta HSD, was localized to the microsomal fraction of liver and was concentrated in pericentral locations. Immunoreactive protein was not detected in liver of immature (before 25 days of age) rats of either sex or in adult female liver. Northern blot analysis of liver and testicular RNA with a rat testicular 3 beta HSD cDNA probe revealed the presence of a 1.6-kilobase mRNA species in addition to the major 2.1-kilobase mRNA species in adult male liver, neither of which was detected in immature or adult female liver RNA. Hypophysectomy of female rats or treatment with testosterone implants caused induction of liver 3 beta HSD protein, while continuous infusion of GH to male rats decreased the level of 3 beta HSD protein. Similarly, the levels of the mRNA species were decreased after GH treatment. Using [3 alpha-3H]dehydroepiandrosterone as substrate for 3 beta HSD activity, we determined the apparent Km for liver microsomal NAD(+)-dependent 3 beta HSD activity to be 20 microM in both adult male and female liver and was much greater than the Km of rat Leydig tumor 3 beta HSD activity (0.2 microM). Liver 3 beta HSD activity was inhibited by trilostane, a proven inhibitor of gonadal and adrenal 3 beta HSD activity. A rat liver 3 beta HSD cDNA was isolated from a male liver cDNA library that was closely related to the type II 3 beta HSD form of rat ovary but different from type III liver 3 beta HSD. The enzyme obtained upon expression of this cDNA had properties characteristic of male-specific NAD(+)-dependent liver microsomal 3 beta HSD (i.e. high apparent Km for dehydroepiandrosterone) and distinct from those of the high affinity gonadal type I 3 beta HSD.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Hydroxysteroid Dehydrogenases↗
PubMed1998

Dual effects of anti-inflammatory 2-arylpropionic acid derivatives on a major isoform of human liver 3alpha-hydroxysteroid dehydrogenase.

Nonsteroidal anti-inflammatory drugs have been shown to be potent inhibitors of mammalian 3alpha-hydroxysteroid dehydrogenase. Here, we report that the drugs of the 2-arylpropionic acid class act as both activators and inhibitors for a predominant isoform of the human liver enzyme which is involved in the metabolism of steroid hormones, bile acids, drug ketones and xenobiotic aromatic hydrocarbons. Flurbiprofen, fenoprofen, ibuprofen, naproxen, ketoprofen and suprofen stimulated the activity of the human enzyme (1.5-2.4-fold) at low concentrations of less than 20-100 microM, whereas at higher concentrations they inhibited the activity. Comparison of the effects of the structurally related compounds with the drugs revealed that the essential structure required as the activator molecule is 2-phenylpropionic acid with a hydrophobic substituent on the aromatic ring. In addition, an R-enantiomer of ibuprofen showed higher activation (3-fold) than its S-enantiomer. Kinetic analysis with respect to NADP+ concentration indicated that R- and S-ibuprofens are nonessential activators showing binding constants of 23 and 34 microM, respectively. Neither enantiomers activated, but rather inhibited the enzyme, with Met replacing Arg-276 which has been shown to interact with the 2'-phosphate of NADP+. The inhibitions of the mutant enzyme by R- and S-ibuprofens were competitive with respect to the substrate, giving Ki values of 95 and 18 microM, respectively. The results suggest that the human liver 3alpha-hydroxysteroid dehydrogenase isoform possesses the two distinct sites, activator and inhibitor sites, to which anti-inflammatory 2-arylpropionates stereoselectively bind.

Alcohol Oxidoreductases↗
PubMed1983

Participation of cytochrome b5 electron transport system coupled with delta 5-3 beta-hydroxysteroid dehydrogenase on cytochrome P-450 monooxygenase reactions of guinea pig adrenal microsomes.

Not only cytochrome P-450 and cytochrome P-450 reductase, but considerable amount of cytochrome b5 and cytochrome b5 reductase were also contained in the adrenal microsomes of guinea pig. Addition of nicotinamide adenine dinucleotide (NADH) stimulates the activities of cytochrome P-450 monooxygenases such as 21-hydroxylase, 17 alpha-hydroxylase and C17,20 lyase supported with nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor. In addition, substrate for delta 5-3 beta-hydroxysteroid dehydrogenase plus NAD+ also stimulate the same cytochrome P-450 monooxygenase activities. These observations were suggesting the participation of cytochrome b5 electron transport system on cytochrome P-450 monooxygenase (21-hydroxylase, 17 alpha-hydroxylase and C17,20 lyase) reactions associated with the biosynthesis of corticoids and adrenal androgens. Furthermore, it is also suggesting that cytochrome b5 electron transport system involves the reaction of delta 5-3 beta-hydroxysteroid dehydrogenase.

3-Hydroxysteroid Dehydrogenases↗
PubMed1993

A case of late-onset congenital adrenal hyperplasia due to partial 3 beta-hydroxysteroid dehydrogenase deficiency.

Late-onset congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency has been reported with increasing frequency, but only a few adult women have been found to have this disorder in Japan. We report a 26-year-old Japanese hirsute woman with partial 3 beta-hydroxysteroid dehydrogenase deficiency. The diagnosis was based on significantly increased ratios of 17-hydroxypregnenolone to 17-hydroxyprogesterone and of dehydroepiandrosterone to androstenedione after administration of ACTH. Hirsutism improved with the administration of dexamethasone (0.5 mg) every evening. Since routine assay of delta 5-steroid metabolites has become available, the incidence of this disorder will increase. Diagnostic effort should be attempted since the disorder is treatable with low-dose dexamethasone.

3-Hydroxysteroid Dehydrogenases↗
PubMed1980

A further study of 17 beta-hydroxysteroid oxidoreductase in the human testis: mechanism of in vitro activation.

The mechanism and specificity of product activation of 17 beta-hydroxysteroid oxidoreductase for interconversion of androstenedione and testosterone were investigated using cell-free homogenates of human testes as an enzyme preparation. The reactions of oxidation and reduction catalyzed by the enzyme followed the Michaelis-Menten formula Addition of testosterone to the incubation medium resulted in increased Vmax and decreased the Km of reductase function of the enzyme. Androstenedione added to the incubation medium increased both Vmax and Km of the enzyme for the oxidase function. The apparent Km of the reductase function for [3H] androstenedione as a substrate in the presence of a fixed concentration of [14C] testosterone was found identical with the apparent Kd for the androstenedione as an effector (activator) for the oxidase function of the enzyme calculated from the simultaneous increase of [14C] androstnedione produced from the fixed concentration of [14C] testosterone. Similarly, the apparent Km of the oxidase function for [3H] testosterone as a substrate in the presence of a fixed concentration of [14C] androstenedione was identical to the apparent Kd for the testosterone as an effector (activator) for the reductase function of the enzyme calculated from the simultaneous increase of [14C] testosterone produced from the fixed concentration of [14C] androstenedione. None of the free 17-oxo and 17 beta-hydroxy steroids examined showed substrate activation or product inhibition of the enzyme except for androstenedione which showed product inhibition at high concentration. The present findings in combination with our previous data suggest the presence of two sites on the 17 beta-hydroxysteroid oxidoreductase of the human testis, one specific for androstenedione and the other specific for testosterone, each serving as an active site for the substrate and also as an activation site for the other active site.

17-Hydroxysteroid Dehydrogenases↗