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

After i.m. injection of [3H]butyrobetaine into intact and castrated rats, the specific activity of plasma carnitine remained nearly constant over 24--96 h and epididymal uptake of carnitine was constant per unit time up to 72 h. The uptake ratio of intact to castrated rats was high at 48, 72 and 96 h after injection. Administration of estradiol valerate over 20 days reduced carnitine uptake in epididymis. This reduction was dose-dependent when estrogen was administered i.m. at 0.33--10 microgram/day levels. A maximum reduction of 90% was obtained with the 10 microgram dose. A dose increase from 33 to 100 microgram/day caused no further reduction. Norspiroxenone (2--10 mg/day) and SK 7670 (1.5 and 7.5 mg/day) were less effective than estradiol valerate (10 microgram/day) in suppressing carnitine uptake in epididymis. Epididymal carnitine uptake in estradiol valerate treated rats (33 microgram/day for 20 days) increased in a time- and dose-dependent manner under testosterone propionate treatment (50, 250, 1250 microgram/day). Carnitine uptake increased to 80% of the nonsuppressed levels when testosterone propionate was adminsitered over a 6-day period at 1250 microgram/day. Dihydrotestosterone increased epididymal carnitine uptake to the same extent as testosterone propionate. delta4-androstene-3,17-dione and 5alpha-androstane-3alpha,17beta-diol (50 microgram/day) were less effective, stimulating uptake to only 15% and 40% respectively of the testosterone propionate (250 microgram/day) stimulated levels. Changes in epididymal carnitine uptake evoked by various experimental procedures were closely paralleled by weight changes in the ventral prostate. This response resemblance indicates a similarity between the androgen sensitivity of the prostate gland and that of the carnitine uptake system in epididymis. The dose-dependent effect of estrogen on the accumulation of epididymal carnitine, together with the marked responses induced in this system by manipulation of its androgen status, support a possible use for the system as an assay for androgen or antiandrogen potency in vivo.
Mol Cell Endocrinol
PMID:Accumulation of carnitine in rat epididymis after injection of [3H]butyrobetaine in vivo: quantitative aspects, and the effects of androgens and antiandrogens. 68 Mar 41

The relative binding affinity of several androstane- and C-19-nor-androstane-compounds for the estradiol (E2)-receptor in human myometrial and mammary cancer tissue was studied. High speed cytosol was incubated with tritiated E2 alone as well as in the presence of increasing amounts of the compound to be tested. The highest affinity is found for steroids with two hydroxyl-groups at C-3 and C-17 in the beta-position and a double bond at C-4-5 or C-5-6. Saturation of the A-ring decreases the affinity: 5alpha-compounds have less affinity, 5-beta-compounds have less affinity; 5beta-compounds hardly any affinity. The presence of a hydroxyl-group in the 3alpha, 11beta or 16beta-position decreases the affinity, as dose a 3-oxo or 17-oxo-group. Removal of the C-19-methyl-group facilitates the binding. This data led to the concept that flatness of the A-ring in respect to the B-ring of the steroid molecule is a principal requirement for binding to the E2-receptor. The rank order of RBA is identical in myometrium and in mammary cancer tissue, indicating that estrogen-receptors are at least highly similar in both target tissues.
Mol Cell Endocrinol 1977 Jul
PMID:Relative binding affinity of androstane and C-19-nor-androstane-steroids for the estradiol-receptor in human myometrial and mammary cancer tissue. 88 Nov 4

Metabolic transformations of progesterone in cultures of granulosa cells from immature hypophysectomized rats treated with diethylstilbestrol were studied in relation to the synergistic action of exogenous androgen and FSH on progestin (progesterone and 20alpha-dihydroprogesterone) accumulation. Androstenedione (Ad; 10 ng/ml) enhanced the sensitivity of rat granulosa cells to this steroidogenic action of FSH, lowering the threshold of the response from greater than 4 ng/ml (FSH alone) to 0.8 ng/ml in the presence of Ad. A synergistic effect with FSH was also shown by various 5alpha-androstane derivatives. They were, however, less effective than the parent delta4-3 keto androstenes. Progesterone underwent extensive 5alpha-reduction during culture, leading to accumulation of endogenous 5alpha-pregnane compounds, and to transformation of labelled progesterone into 5 alpha-reduced radiometabolites. These compounds corresponded in gas-liquid and thin-layer chromatographic behaviour to 3alpha-hydroxy-5alpha-pregnan-20-one, 20alpha-hydroxy-5alpha-pregnan-3-one and 5alpha-pregnane-3alpha,20alpha-diol. The rate of 5alpha-reduction of progestins was not affected by the presence of exogenous Ad (1 microgram/ml), ruling out the possibility that the effect of androgen on progestin accumulation depends on competitive inhibition of 5alpha-reductase. An involvement of androgen of thecal origin in the enhancement of the sensitivity of the FSH-responsive mechanism in granulosa cells is suggested.
Mol Cell Endocrinol 1977 Sep
PMID:Studies on the synergistic effect of androgen on the stimulation of progestin secretion by FSH in cultured rat granulosa cells: progesterone metabolism and the effect of androgens. 92 13

Recent reports have thrown doubt on the role of measurements of plasma 5 alpha-androstane-3 alpha,17 beta-diol glucuronide (3 alpha-diolG) as a marker of peripheral androgen metabolism in women with polycystic ovarian syndrome and idiopathic hirsutism. It has been suggested that a plasma profile of C19 steroid glucuronides may be more informative. While preliminary data indicates that both 3 alpha-diolG and androsterone G (ADTG) may arise from adrenal steroid precursors, there have been no reports of C19 steroid glucuronides in women with non-classical, or late-onset congenital adrenal hyperplasia (NC-CAH), who constitute a significant proportion of the hirsute female population. We therefore measured plasma levels of 3 alpha-diolG, ADTG and dihydrotestosterone G (DHTG) before and following a standard Cortrosyn test in 15 symptomatic and 3 asymptomatic NC-CAH patients, 5 heterozygote carriers for 21-hydroxylase deficiency (NCHETS) and 18 normal women. The effects of chronic glucocorticoid (GCR) therapy (greater than 3 months) on the C19 steroid glucuronide profile in the symptomatic patients was also investigated. Baseline plasma levels of all 3 glucuronides were significantly (P less than 0.001) higher in symptomatic patients compared with either normals or NCHETS. However, the order of discrimination was ADTG greater than 3 alpha-diolG greater than DHTG. There were no significant differences between steroid glucuronide levels for NCHET and normal women and the C19 steroid glucuronide concentrations for the asymptomatic NC-CAH patients were greater than 2 SD above the normal means. Moderate clinical improvement was observed in all patients receiving oral GCR therapy and was accompanied by approx. 80% suppression of the plasma levels of all 3 C19 steroid glucuronides. This contrasts with a mean suppression of androstenedione of only 50%. However, plasma levels of the C19 steroid glucuronides were not significantly increased in response to a short ACTH stimulation test. This may be explained by the fact that the androgen glucuronides are thought to be peripherally formed metabolites derived from unconjugated glandular secreted androgen precursors and thus their synthesis at 60 min following adrenal stimulation may lag substantially behind that of their respective precursors. There were significant linear correlations between the levels of all 3 glucuronides, but neither correlated with Ferriman-Gallway scores, body mass index or 17-hydroxyprogesterone levels.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1992 Apr
PMID:Plasma levels of C19 steroid glucuronides in pre-menopausal women with non-classical congenital adrenal hyperplasia. 131 40

A series of 17 beta-acylurea-4-aza-5 alpha-androstan-3-one derivatives has been assayed in vitro as inhibitors of testosterone 5 alpha-reductase, using the particulate fraction of human hyperplastic prostate and rat prostate as enzyme sources. The most active derivatives were 1-[4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carbonyl]- 1,3-dicyclohexylurea (compound 1) and 1-[4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carbonyl]- 1,3-diisopropylurea (compound 3) which demonstrated IC50 values of 41 and 55 nM for the human enzyme and of 83 and 53 nM for the rat enzyme, respectively. Neither compound showed any relevant binding affinity to the rat prostate androgen receptor (IC50 of approximately 100 and 84 microM). When given orally in immature castrated rats together with subcutaneous testosterone propionate (TP) for 7 consecutive days, compound 3 (laboratory code FCE 26073), at 3 mg/kg/day, significantly decreased the ventral prostate growth promoting effect of TP by 40-50%, whereas compound 1 was ineffective up to the dose of 10 mg/kg/day.
J Steroid Biochem Mol Biol 1992 Mar
PMID:17 beta-acylurea derivatives of 4-azasteroids as inhibitors of testosterone 5 alpha-reductase. 137 5

In ovariectomized estrogen-primed rats, progesterone as well as 5 alpha-dihydroprogesterone (5 alpha-DHP) are capable of inducing the release of gonadotropins. This study examined the need of 5 alpha-reduction as a prerequisite for the action of progesterone. The 5 alpha-reductase inhibitor, N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide was injected at a 1 or 2 mg dose/rat 2 h prior to an injection of 0.4 or 0.8 mg progesterone/kg body weight at 0900 h to immature ovariectomized, estrogen-primed rats and serum was analyzed for LH and FSH at 1500 h. Pituitary and hypothalamic 5 alpha-reductase activity was measured at the time of progesterone administration and at the time of the surge by incubating tissue homogenates with [3H]progesterone. Substrate, ([3H]progesterone) and product ([3H]5 alpha-DHP), were separated by reverse phase HPLC. The pituitary 5 alpha-reductase activity was not blocked at 1500 h. However, both pituitary and hypothalamic 5 alpha-reductase was blocked at the time of progesterone administration. No effect was seen by acute administration of the 5 alpha-reductase inhibitor upon either the 0.4 or 0.8 mg progesterone/kg-induced release of LH and FSH. There was, however, a specific, significant inhibition of progesterone-induced FSH but not LH release when the 5 alpha-reductase inhibition was sustained throughout the afternoon of the gonadotropin surge. These results indicate a biologically significant role for the irreversible 5 alpha-reduction of progesterone in the modulation of the release of FSH.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Role of 5 alpha-reduction in progesterone's ability to release FSH in estrogen-primed ovariectomized rats. 138 45

Primates are unique in having adrenals that secrete large amounts of the precursor sex steroids (PSS) dehydroepiandrosterone (DHEA) and especially DHEA-sulfate. The adrenal PSS require the action of 3 beta-hydroxysteroid dehydrogenase/5-ene-4 ene isomerase (3 beta-HSD), 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), 5 alpha-reductase and/or aromatase to form the androgen dihydrotestosterone (DHT) or the estrogens 17 beta-estradiol and androst-5-ene-diol. Knowing the crucial role of 3 beta-HSD and 17 beta-HSD in sex steroid biosynthesis both in classical as well as in peripheral steroidogenic tissues, we have concentrated our efforts on the elucidation of the molecular structure of these enzyme families. We have thus characterized two types of human 3 beta-HSD cDNA clones and their corresponding genes which encode deduced proteins of 371 and 372 amino acids and share 93.5% homology. Human type I 3 beta-HSD is the almost exclusive mRNA species expressed in the placenta and skin, while human type II is the predominant mRNA species in the adrenals, ovaries and testes. We have also recently elucidated the structure of three types of rat 3 beta-HSD cDNAs which all encode a 372 amino acid protein. The predicted rat type I and II 3 beta-HSD proteins expressed adrenals, gonads and adipose tissue share 94% homology while they share 80% similarity with the liver-specific type III 3 beta-HSD. Transient expression of human type I and II as well as rat type I and II 3 beta-HSD cDNAs in HeLa human cervical carcinoma cells reveals that 3 beta-ol dehydrogenase and 5-ene-4-ene isomerase activities reside within a single protein and that these cDNAs encode functional 3 beta-HSD proteins. The expressed rat type III protein possesses a unique property catalyzing selectively the reduction of 3 beta-androstane 5 alpha-steroids such as DHT. Furthermore, we have also demonstrated by site-directed mutagenesis that the lower activity of expressed rat type II compared to rat type I 3 beta-HSD protein is due to a change of four amino acid residues potentially involved in a membrane-spanning domain. In parallel, we have characterized the complete nucleotide sequence of human 17 beta-HSD cDNA clones encoding a 327 amino acid protein as well as two in tandem 17 beta-HSD genes. Two major 17 beta-HSD mRNA species have been detected in several tissues due to a tissue-specific alternative site of initiation of transcription.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1992 Oct
PMID:Ontogeny and subcellular localization of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) in the human and rat adrenal, ovary and testis. 139 Feb 95

We recently showed that the production of progesterone (P4) in human placental explant culture from early gestation is enhanced by treatment with 19-nortestosterone (19-NT) or with certain androgens, namely androstenedione (A-dione), 5 alpha-androstane-3 alpha,17 beta diol (3 alpha-diol) and 5 alpha-androstane-3 beta,17 beta diol (3 beta-diol). This stimulation of P4 was explored further in this study. There was little metabolism of radioactive P4 when incubated for 24 h in the presence or absence of these steroids. The role of different steroids in the regulation of P450 cholesterol side-chain cleavage enzyme (P450scc) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) was evaluated by measuring the conversion of P4 derived from unlabelled 25-hydroxycholesterol and from labelled pregnenolone, respectively. The results showed that 19-NT, A-dione and 3 alpha-diol stimulated P450scc activity; however, 3 beta-diol was ineffective. While 19-NT and 3 beta-diol enhanced the bioconversion of pregnenolone to P4, A-dione and 3 alpha-diol were without effect. The initial rapid stimulation of P4 by 19-NT within 2 h of incubation was not blocked by concurrent treatment with cycloheximide (CH). However, after incubation for 24 h, 70% of the 19-NT-stimulated P4 was abolished by CH. During the same incubation period, P4 stimulation by A-dione, 3 alpha- and 3 beta-diol were completely blocked by treatment with CH. Thus our observations suggest that 19-NT-stimulated P4 accumulation is due to the combined effects on P450scc and 3 beta-HSD enzyme activities. A-dione and 3 alpha-diol increase biosynthesis of P4 by acting selectively on P450scc enzyme. However, the stimulatory action of 3 beta-diol on P4 is only at the level of 3 beta-HSD. Since CH blocks the stimulatory actions, the mechanism(s) by which androgens (A-dione, 3 alpha-diol and 3 beta-diol) and norandrogen (19-NT) augment the biosynthetic enzyme activities appears to be mediated by a process inhibited by CH. Since CH interference was absent during the initial rapid P4-stimulation by 19-NT, there may be a direct action of this steroid at the cellular level which is not dependent on new protein synthesis.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Influence of 19-nortestosterone and androgens on progesterone biosynthetic enzymes in early human placental explants. 152 44

In earlier studies, two distinct molecules, 20 alpha-HSD-I and 20 alpha-HSD-II, responsible for 20 alpha-HSD activity of pig adrenal cytosol were purified to homogeneity and characterized [S. Nakajin et al., J. Steroid Biochem. 33 (1989) 1181-1189]. We report here that the purified 20 alpha-HSD-I, which mainly catalyzes the reduction of 17 alpha-hydroxyprogesterone to 17 alpha,20 alpha-dihydroxy-4-pregnen-3-one, catalyzes 3 alpha-hydroxysteroid oxidoreductase activity for 5 alpha (or 5 beta)-androstanes (C19), 5 alpha (or 5 beta)-pregnanes (C21) in the presence of NADPH as the preferred cofactor. The purified enzyme has a preference for the 5 alpha (or 5 beta)-androstane substrates rather than 5 alpha (or 5 beta)-pregnane substrates, and the 5 beta-isomers rather than 5 alpha-isomers, respectively. Kinetic constants in the reduction for 5 alpha-androstanedione (Km; 3.3 microM, Vmax; 69.7 nmol/min/mg) and 5 beta-androstanedione (Km; 7.7 microM, Vmax; 135.7 nmol/min/mg) were demonstrated for comparison with those for 17 alpha-hydroxyprogesterone (Km; 26.2 microM, Vmax; 1.3 nmol/min/mg) which is a substrate for 20 alpha-HSD activity. Regarding oxidation, the apparent Km and Vmax values for 3 alpha-hydroxy-5 alpha-androstan-17-one were 1.7 microM and 43.2 nmol/min/mg, and 1.2 microM and 32.1 nmol/min/mg for 3 alpha-hydroxy-5 beta-androstan-17-one, respectively. 20 alpha-HSD activity in the reduction of 17 alpha-hydroxyprogesterone catalyzed by the purified enzyme was inhibited competitively by addition of 5 alpha-DHT with a Ki value of 2.0 microM. Furthermore, 17 alpha-hydroxyprogesterone inhibited competitively 3 alpha-HSD activity with a Ki value of 150 microM.
J Steroid Biochem Mol Biol 1992 Feb
PMID:3 alpha-hydroxysteroid dehydrogenase activity catalyzed by purified pig adrenal 20 alpha-hydroxysteroid dehydrogenase. 154 86

By means of high performance liquid chromatography and gas chromatography-mass spectrometry it has been found that 5 alpha-androstane-3 beta,17 beta-diol sulfate and 3 beta-hydroxy-5 alpha-androstan-17-one sulfate (epiandrosterone) are major secretory steroids of the mature boar testes. These same compounds were similarly identified in culture media when porcine Leydig cells were incubated with androstenedione as substrate. In addition, they were seen as the principal secretory products when [3H]androstenedione and [3H]testosterone were used as substrates; and their presence was greatly reduced by an inhibitor of 5 alpha-reductase (N,N-diethyl,4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide). Greater quantities of 5 alpha-androstanediol than epiandrosterone were noted in all instances. These findings provide further evidence of the versatile activity of the boar testes in steroidogenesis.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Identification of 5 alpha-androstane-3 beta,17 beta-diol and 3 beta-hydroxy-5 alpha-androstan-17-one sulfates as quantitatively significant secretory products of porcine Leydig cells and their presence in testicular venous blood. 155 16


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