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Query: UNIPROT:P06889 (Mol)
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Two Bacillus strains were isolated from the foregut of the water beetle Agabus affinis (Payk.) and tested for their steroid transforming ability. After incubation with androst-4-en-3,17-dione (AD), 13 different transformation products were detected. AD was hydroxylated at C6, C7, C11 and C14, resulting in formation of 6beta-, 7alpha-, 11alpha- and 14alpha-hydroxy-AD. One strain also produced small amounts of 6beta,14alpha-dihydroxy-AD. Partly, the 6beta-hydroxy group was further oxidized to the corresponding 6-oxo steroids. In addition, a specific reduction of the delta4-double bond was observed, leading to the formation of 5alpha-androstane derivatives. In minor yields the carbonyl functions at C3 and C17 were reduced leading to the formation of 3zeta-OH or 17beta-OH steroids. EI mass spectra of the trimethylsilyl and O-methyloxime trimethylsilyl ether derivatives of some transformation products are presented for the first time.
J Steroid Biochem Mol Biol 1998 Dec
PMID:Transformation of steroids by Bacillus strains isolated from the foregut of water beetles (Coleoptera:Dytiscidae): I. Metabolism of androst-4-en-3,17-dione (AD). 1003 Jun 95

The glucuronidation of steroid hormones is catalyzed by a family of UDP-glucuronosyltransferase (UGT) enzymes. Previously, two cDNA clones, UGT2B15 and UGT2B17, which encode UGT enzymes capable of glucuronidating C19steroids, were isolated and characterized. These proteins are 95% identical in primary structure; however, UGT2B17 is capable of conjugating C19steroid molecules at both the 3alpha and 17beta-OH positions, whereas UGT2B15 is only active at the 17beta-OH position. To identify the amino acid residue(s) which may account for this difference in substrate specificity, a comprehensive study on the role of 15 residues which differ between UGT2B15 and UGT2B17 was performed by site-directed mutagenesis. The stable expression of UGT2B17 mutant proteins into HK293 cells demonstrated that the mutation of isoleucine 125, valine 181 and valine 455 to the residues found in UGT2B15 did not alter enzyme activity nor substrate specificity. Furthermore, mutation of the variant residues in UGT2B15 (serine 124, asparagine 125, phenylalanine 165) to the amino acid residues found in UGT2B17 did not alter enzyme activity nor substrate specificity. However, mutation of the serine residue at position 121 of UGT2B17 to a tyrosine, as found in UGT2B15, abolished the ability of UGT2B17 to conjugate androsterone at the 3alpha position, but still retained activity for dihydrotestosterone and 5alpha-androstane-3alpha, 17beta-diol, which have an OH-group at the 17beta position. Interestingly, mutation of tyrosine 121 in UGT2B15 to a serine abolished activity for C19steroids. It is suggested that the serine residue at position 121 in UGT2B17 is required for activity towards the 3alpha and not for the 17beta position of C19steroids, whereas the tyrosine 121 in UGT2B15 is necessary for UGT activity. Despite the high homology between UGT2B15 and UGT2B17, it is apparent that different amino acid residues in the two proteins are required to confer conjugation of C19steroid molecules.
J Mol Biol 1999 May 28
PMID:Alteration of human UDP-glucuronosyltransferase UGT2B17 regio-specificity by a single amino acid substitution. 1033 3

Upon androgen deprivation, Shionogi (SC-115) mouse mammary tumors undergo phenotypic changes enabling their escape from growth dependence on androgens. Even within androgen-responsive cell populations, marked clonal heterogeneity is observed in the trophic effects of androgens. The present study compares several parameters of androgen action between three SC-115 cell clonal subpopulations exhibiting high (clone 107), low (clone S1A2) and no trophic response (clone 415) to androgens. These parameters pertain to (1) kinetics of androgen binding, (2) metabolism of 5alpha-dihydrotestosterone (DHT), 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) and 5alpha-androstane-3beta,17beta-diol (3beta-diol), (3) ornithine decarboxylase (ODC) activity and (4) interleukin-1alpha (IL-1alpha) action on cell proliferation. Only marginal differences in the affinity and abundance of androgen-specific binding sites were detected between the three clones. While clone S1A2 degraded DHT to 3alpha-diol at a much faster rate than the highly androgen-sensitive 107 cells and androgen-insensitive 415 cells, differences in the rates of intracrine conversion of 3alpha-diol and 3beta-diol to DHT did not correlate with the ability of these steroids to stimulate cell proliferation. Induction of ODC activity at the onset of exponential growth was strongly DHT-dependent in 107 cells, whereas this dependence was markedly attenuated in androgen-hyposensitive cells. Unexpectedly, DHT strongly repressed the marked ODC induction resulting from fresh medium addition in 415 cells which show no growth response to androgens. Low IL-1alpha concentrations were mitogenic in all three SC-115 clones. Whereas the mitogenic action of IL-1alpha was completely androgen-dependent in 107 cells, this dependence was relieved in S1A2 cells, which responded to DHT and IL-1alpha in an additive fashion. Thus, clonal heterogeneity in the pattern of steroid metabolism within Shionogi tumors cannot solely account for loss of androgen dependence, which may rather correlate with the constitutive activation of transduction pathways controlling the expression of growth-associated genes (e.g. ODC) by serum growth factors, including IL-1alpha.
J Steroid Biochem Mol Biol 1999 Nov
PMID:Differential androgen sensitivity is associated with clonal heterogeneity in steroid metabolism, ornithine decarboxylase regulation and IL-1alpha action in mouse mammary tumor cells. 1061 59

Besides their clinical uses, anabolic steroids (AASs) are self-administered by athletes to improve muscle mass and sports performance. The biological basis for their presumed effectiveness at suprapharmacological doses, however, remains uncertain. Since the expression of high levels of some stress proteins (HSPs) has been associated with an increased tolerance to stress and chronic exercise up-regulates HSP72 in skeletal muscle, this investigation was aimed at testing whether the administration of suprapharmacological doses of AASs, either alone or in conjunction with chronic exercise, induced changes in HSP72. Nandrolone decanoate (ND), an estrene derivative, but not stanozolol (ST), a derivative of the androstane series, up-regulated the levels of HSP72 and changed the proportions of various charge variants of the cytosolic HSP70s in sedentary and exercise-trained rats, exclusively in fast-twitch fibres. Since the expression of HSP73-levels in skeletal muscle was dependent on gender but not on muscle type, and that of HSP72-levels was muscle type specific but gender-independent, ND effects on cytosolic HSP70s could not be explained solely by a functional relationship with sex steroids. The reported results indicate that, by up-regulating the expression levels of HSP72 in fast-twitch fibres, nandrolone decanoate could contribute to improving the tolerance of skeletal muscle to high-intensity training.
J Steroid Biochem Mol Biol 2000 Sep
PMID:Anabolic steroid and gender-dependent modulation of cytosolic HSP70s in fast- and slow-twitch skeletal muscle. 1107 57

Formestane (Lentaron(R), 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.) injection. To investigate the pharmacokinetics, bioavailability and metabolism of the drug, seven patients received single 250 mg i.m. doses of commercial formestane on Days 0, 21, 35, 49 and 63 of this trial. On Day 63, three of the patients received an additional single intravenous (i.v.) pulse dose of 1 mg of 14C-labelled formestane. The plasma kinetics after i.m. dosing confirmed a sustained release of formestane from the site of injection. Within 24-48 h of the first dose, the circulating drug reached a C(max) of 48.0+/-20.9 nmol/l (mean+/-S.D.; N=7). At the end of the dosing interval, after 14 days, the plasma concentration was still at 2.3+/-1.8 nmol/l. The kinetic variables did not significantly change during prolonged treatment. Intramuscular doses appear to be fully bioavailable. Following i.v. injection of 14C-formestane, the unchanged drug disappeared rapidly from plasma, the terminal elimination half-life being 18+/-2 min (N=3). Plasma clearance, CL was 4.2+/-1.3 l/(h kg) and the terminal distribution volume V(z) was 1.8+/-0.5 l/kg. The drug is mainly eliminated by metabolism, renal excretion of metabolites accounting for 95% of dose. The excretory balance of 14C-compounds in urine and faeces totals up to 98.9+/-0.8% of the i.v. dose after 168 h. The 14C-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucuronide of formestane. The other two represent 3-O-sulfates of the exocons 3beta,4beta-dihydroxy-5alpha-androstane-17-one and 3alpha,4beta-dihydroxy-5alpha-androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction, accompanied by reduction of the 4,5-enol function. The exocons do not inhibit human placental aromatase activity in vitro.
J Steroid Biochem Mol Biol 2001 Apr
PMID:Pharmacokinetics and metabolism of formestane in breast cancer patients. 1135 73

The 11-cis retinol dehydrogenase (11-cis-RoDH) enzyme catalyzes the oxidation of cis-retinols to their respective retinals, a rate limiting step in the formation of retinoic acids. Earlier, we have shown that the enzyme also exhibits an oxidative 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) activity that can convert 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) into dihydrotestosterone (DHT), the most potent natural androgen. 11-cis-RoDH could thus control the formation of two active hormones, namely 9-cis retinoic acid and DHT. Therefore, depending upon the substrate availability in the various tissues, this enzyme could provide different metabolites for specific cell functions. To further investigate the role of 11-cis-RoDH in the formation of DHT from 3alpha-diol, we stably expressed the enzyme in the human embryonic kidney cell line 293 (HEK-293). The transformation of 3alpha-diol by these cells was evaluated by assays using both microsomal fractions and intact cultured cells stably expressing 11-cis-RoDH. The results show that in the intact cells 11-cis-RoDH only catalyzes the oxidation of 3alpha-diol into DHT whereas the microsomal fraction catalyzes both the oxidation and the reduction reactions depending upon whether NAD(+) or NADH is added. Furthermore, we examined the ability of 11-cis-RoDH, through the production from 3alpha-diol of the active androgen DHT, to activate the androgen-responsive promoter of the prostate-specific antigen (PSA) gene. The co-transfection of the pCMV expression vector containing 11-cis-RoDH (pCMV-11-cisRoDH), a luciferase reporter gene driven by a PSA promoter (pCMV-PSA-Luc) and an androgen receptor (pCMV-hAR) showed that, in the presence of 3alpha-diol, the expression of the PSA promoter is increased by five to six-fold. Moreover, this stimulatory effect is inhibited by hydroxyflutamide, a well-known antiandrogen. These results suggest that 11-cis-RoDH could be involved in a non-classical pathway of androgen formation and might play a role in the modulation of the androgenic response in some peripheral tissues.
J Steroid Biochem Mol Biol 2001 May
PMID:Modulation of the androgenic response by recombinant human 11-cis retinol dehydrogenase. 1137 78

The androgen 5alpha-androstane-3alpha,17beta-diol (5alpha-adiol) is synthesized in testes and secreted into plasma of male tammar wallaby pouch young and appears to virilize the urogenital sinus. To provide insight into its mechanism of action, a dose response study showed that administration of 1 microg 5alpha-adiol monoenanthate per g body wt. per week for 3 weeks to 24-day-old female pouch young induced prostate bud formation equivalent to that of males of the same age. Administration of this same dose of the enanthates of testosterone, dihydrotestosterone, and 5alpha-adiol to female pouch young caused equivalent virilization of the urogenital sinus. The fact that 5alpha-adiol does not exert a unique effect, together with our earlier findings in this species that 5alpha-adiol and testosterone are converted to dihydrotestosterone in the urogenital sinus and that virilization of the urogenital sinus is prevented by the androgen receptor antagonist flutamide, suggest that 5alpha-adiol is a circulating precursor for dihydrotestosterone formation in this tissue.
Mol Cell Endocrinol 2001 Jul 05
PMID:Virilization of the urogenital sinus of the tammar wallaby is not unique to 5alpha-androstane-3alpha,17beta-diol. 1147 45

Androgen physiology differs from that of other steroid hormones in two major regards. First, testosterone, the predominant circulating testicular androgen, is both an active hormone and a prohormone for the formation of a more active androgen, the 5alpha-reduced steroid dihydrotestosterone. Genetic evidence indicates that testosterone and dihydrotestosterone work via a common intracellular receptor, and studies involving in vitro reporter gene assays and intact mice in which both steroid 5alpha-reductase isoenzymes have been disrupted by homologous recombination indicate that dihydrotestosterone acts during embryonic life to amplify hormonal signals that can be mediated by testosterone at higher concentrations. However, in post-embryonic life dihydrotestosterone plays unique roles that have not been elucidated. Studies of other 5alpha-reduced steroids, including the plant hormone brassinolide, the hog pheromones androstanol and androstenol, and 5alpha-dihydroprogesterone (in horses and elephants) indicate that this reaction serves different functions in different systems. Second, during embryonic life androgen causes the formation of the male urogenital tract and hence is responsible for development of the tissues that serve as the major sites of androgen action in postnatal life. It has been generally assumed that androgens virilize the male fetus by the same mechanisms as in the adult, namely by the conversion of circulating testosterone to dihydrotestosterone in target tissues. However, in marsupial mammals there is no sexual dimorphism in the levels of testosterone or dihydrotestosterone at the time the male phenotype forms, and in the pouch young of one marsupial, the tammar wallaby, the testes secrete another 5alpha-reduced steroid, 5alpha-androstane-3alpha, 17beta-diol (5alpha-adiol), into plasma. The administration of 5alpha-adiol to female pouch young causes profound virilization of the urogenital sinus and external genitalia, but within target tissues 5alpha-adiol appears to work after oxidation to dihydrotestosterone. Thus, two separate mechanisms evolved for the formation of dihydrotestosterone in target tissues. 5alpha-adiol is the predominant androgen in neonatal testes in several placental mammals, but it is unclear whether it plays a similar role in other mammalian species.
Mol Cell Endocrinol 2002 Dec 30
PMID:Androgen physiology: unsolved problems at the millennium. 1257 8

In Bufo arenarum, androgen biosynthesis occurs through a complete 5-ene pathway, including 5-androstane-3beta,17beta-diol as the immediate precursor of testosterone. Besides, steroidogenesis changes during the breeding period, turning from androgens to C(21)-steroids such as 5alpha-pregnan-3alpha,20alpha-diol, 3alpha-hydroxy-5alpha-pregnan-20-one and 5alpha-pregnan-3,20-dione. In B. arenarum, steroid hormones are not involved in hCG-induced spermiation, suggesting that the steroidogenic shift to C(21)-steroids during the breeding be not related to spermiation. The activity of 17-hydroxylase-C(17-20) lyase (CypP450(c17)) decreases during the reproductive season, suggesting that this enzyme would represent a key enzyme in the regulation of seasonal changes. However, the increase in the affinity for pregnenolone of 3beta-hydroxysteroid dehydrogenase (3alphaHSD)/isomerase could also be involved. Moreover, the reduction in CypP450(c17) leading to a reduction in C(19)-steroids, among them dehydroepiandrosterone (DHE), would contribute to the conversion of pregnenolone into progesterone, avoiding the non-competitive inhibition exerted by DHE on this transformation. Additionally, CypP450(c17) possesses a higher affinity for pregnenolone than for progesterone, explaining the predominance of the 5-ene pathway for testosterone biosynthesis. Animals in reproductive condition showed a significant reduction in circulating androgens, enhancing the physiological relevance of all the in vitro results. The in vitro effects of mGnRH and hrFSH on testicular steroidogenesis revealed that both hormones inhibited CypP450(c17) activity. In summary, these results demonstrate that, in B. arenarum, the change in testicular steroidogenesis during the reproductive period could be partially due to an FSH and GnRH-induced decrease in CypP450(c17) activity.
J Steroid Biochem Mol Biol 2003 Jun
PMID:Steroid production in toads. 1294 8

Intense research efforts performed during the past decade clearly established the major role of glucuronidation and uridine-diphospho-glucuronosyltransferase (UGT) enzymes for steroid metabolism in humans. However, a clear understanding of the physiological importance of this metabolic process requires in vivo studies. Numerous evidences ascertain that simians are the most appropriate animal models for such studies. Indeed human and monkey have a similar pattern of steroidogenesis, unlike common laboratory mammals such as rat or mouse. Furthermore, human and monkey are unique in having high levels of circulating androsterone glucuronide and androstane-3alpha-diol glucuronide (3alpha-Diol-G). In addition, characterization of eight monkey UGT proteins demonstrated the similarity of their conjugation activity toward steroid hormones. Like human ones, monkey enzymes are expressed in steroid target tissues, where they preferentially glucuronidate androgen and estrogen metabolites. In monkey tissues, immunohistochemical studies demonstrated that UGT2B proteins are expressed in a cell-type specific manner in ovary and kidney, where they control androgens and aldosterone inactivation. These results identify the cynomolgus monkey as an appropriate animal model for the determination of cellular localization of UGT enzymes in steroid target tissues and for the identification of endogenous or exogenous stimuli affecting steroid glucuronidation.
J Steroid Biochem Mol Biol 2003 Jun
PMID:The cynomolgus monkey (Macaca fascicularis) is the best animal model for the study of steroid glucuronidation. 1294 9


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