Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P56851 (epididymal)
 11,273 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the effects of two 4-ene-steroid 5 alpha-reductase inhibitors, diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA) and (4R)-5,10-seco-19-norpregna-4, 5-diene-3,10,20-trione (SECO), on testicular and epididymal androgen biosynthesis. Kinetic analyses revealed that both compounds inhibited epididymal DHT biosynthesis. 4-MA was a competitive inhibitor of epididymal nuclear and microsomal 4-ene-steroid 5 alpha-reductases (3-oxo-5 alpha-steroid: NADP 4-ene-oxidoreductase EC 1.3.1.22) with Kiapp values of 12.8 and 15.1 nmol/l compared to the respective Kmapp values of 185 and 240 nmol/l. Values for the Vmaxapp were always within 70-130% of the control. SECO at 1.0 mumol/l, also inhibited epididymal nuclear and microsomal 4-ene-steroid-5 alpha-reductases, causing respectively 2.9 and 5.2-fold increases in Kmapp. The Vmaxapp values were unchanged. However, SECO concentrations of 5 and 25 mumol/l abolished 4-ene-steroid 5 alpha-reductase activity at all testosterone concentrations. To examine the specificity of these compounds, we investigated their effects on the enzymes that convert pregnenolone to testosterone. Rat testis microsomes converted pregnenolone to testosterone via the 4-ene-3-oxo pathway, with the major metabolites being progesterone, 17-hydroxyprogesterone, 4-androstenedione and testosterone; some 17-hydroxypregnenolone was also formed. Very small amounts of dehydroepiandrosterone (DHA) and 5-androstenediol were detected. SECO, at a concentration that completely inhibited epididymal 4-ene-steroid 5 alpha-reductase activity, did not alter the metabolic profile of pregnenolone metabolism. However, 4-MA prevented the appearance of 4-ene steroids, and large quantities of 17-hydroxypregnenolone and DHA accumulated, suggesting that inhibition of the 3 beta-hydroxysteroid: NAD(P)+ oxidoreductase (EC 1.1.1.51) and 3-oxosteroid 5-ene-4-ene-isomerase (EC 5.3.3.1) [3 beta-hydroxysteroid dehydrogenase-isomerase] was occurring. Optimal conditions for the microsomal conversion of DHA to 4-androstenedione were determined; kinetic analyses of the 3 beta-hydroxysteroid dehydrogenase-isomerase activity revealed that 4-MA inhibited this reaction non-competitively, reducing Vmaxapp values to 25% of the control. The Kiapp determined from the intercept replot, was 121 nmol/l, and the Kmapp was always between 90 and 130% of the control value. It is concluded that SECO is more specific than 4-MA in its effects on androgen biosynthesis in the testis and epididymis and that both these drugs should provide useful tools in assessments of the relative contributions of 5 alpha-reduced androgens to androgen dependent processes.
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PMID:The effects of diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA) and (4R)-5,10-SECO-19-norpregna-4,5-diene-3,10,20-trione (SECO) on androgen biosynthesis in the rat testis and epididymis. 370 62

The entry of total radioactivity into the perfused tubule of the cauda epididymidis was measured during intravenous infusion of labelled steroids into the anaesthetised rat. The effect of altering the composition of the perfusate on this entry and the nature of radiometabolites was also studied. No radioactivity entered the epididymal lumen during infusions of cholesterol, and in the absence of luminal proteins the entry of isotope was generally low (< 14% plasma levels) for all steroids except dehydroepiandrosterone. C21/22-steroids exhibited a delay of about 30 min before a slow rise in luminal activity reached between 3% and 14% plasma levels. For C19-steroids a low plateau level of radioactivity was reached (at 6%-9% plasma levels) with dihydrotestosterone and androstenedione, whereas luminal activity continued to rise with respect to blood during infusions of dehydroepiandrosterone. When protein was added to the perfusing solution the delay in entry of radioactivity was decreased and plateau levels established for C21/22-steroids (at 14%-38% plasma levels). The extents of entry of dihydrotesterone and androstenedione were raised (34%-47%) and radioactivity continued to rise in the lumen relative to blood, but at a faster rate during infusions of dehydroepiandrosterone and perfusion with protein. Testicular fluid protein had little effect on the entry of activity for any steroid. There was no correlation between the extent of entry of tracer with binding of the steroids to plasma or perfusates, or partition into lipids. Tentative identification of metabolites indicated an entry of both dihydrotestosterone and dehydroepiandrosterone during their respective infusions. Androstenedione and androstanediols were excluded whereas 5 alpha-reduced metabolites appeared during of androstenedione and dehydroepiandrosterone.
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PMID:The general importance of proteins and other factors in the transfer of steroids into the rat epididymis. 644 82

When [4-14C]-5 alpha-dihydrotestosterone was incubated with the homogenate of human epididymis, 5 alpha-androstane-3 alpha, 17 beta-diol and 5 alpha-androstane-3 beta, 17 beta-diol were identified as major metabolites. The ratio of 3 alpha- to 3 beta-epimer in androstanediol formation was approximately 2.4. 5 alpha-Androstane-3, 17-dione was also identified as a minor metabolite. Among the subcellular fractions, both the human epididymal 3 alpha- and 3 beta-hydroxysteroid dehydrogenases were localized almost exclusively in the cytosol fraction (105,000 X g supernatant). Both enzymes had optimum pH at 7.5 and optimum temperature at 46 degrees C. NADPH was a more preferable cofactor than NADH for both dehydrogenases. The Michaelis constants (Km) of 3 alpha- and 3 beta-hydroxysteroid dehydrogenase for 5 alpha-dihydrotestosterone were similar and estimated as 8 X 10(-5) M, but the enzymes were unsaturable with the substrate under the conditions investigated, indicating low affinity and high capacity of both dehydrogenases for 5 alpha-dihydrotestosterone. The human epididymal 5 alpha-reductase revealed a regional difference in activity. The 5 alpha-reductase activity in the most proximal part of the head (ductuli efferentes) was one seventh to one tenth the activity in the remaining part of the epididymis which was constructed of ductus epididymis. Except for this finding, the activity of 5 alpha-reductase was highest in the head, then declined along the course to the tail portion. The 5 alpha-reductase for testosterone was competitively inhibited by delta 4-3-oxosteroids such as progesterone, 20 alpha-dihydroprogesterone, 17 alpha-hydroxyprogesterone, 4-androstenedione, 11-deoxycorticosterone, corticosterone and 11-deoxycortisol, which had inhibition constants (Ki) of 3.3 X 10(-9) M, 2.2 X 10(-9) M, 1.8 X 10(-8) M, 1.3 X 10(-8) M, 8.3 X 10(-9) M, 1.5 X 10(-7) M and 8.7 X 10(-8) M, respectively, suggesting the possibility that the 5 alpha-reduction of testosterone is regulated by other delta 4-3-oxosteroids.
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PMID:Studies on the human epididymis: partial characterization of 3 alpha- and 3 beta-hydroxysteroid dehydrogenase, regional distribution of 5 alpha-reductase and inhibitory effect of 4 delta-3-oxosteroids on 5 alpha-reductase. 696 21

Overweight male rats received oral oleoyl-estrone (OE) for 10 days, and were compared with controls. The expression of 17beta-hydroxysteroid dehydrogenase (17betaHSDH) isoenzymes, and other proteins related to sex hormone metabolism, were analyzed in testicle, liver, adrenals and two white adipose sites: subcutaneous inguinal and epididymal pads using a semiquantitative RT-PCR method. Androstenedione, testosterone, estrone and estradiol levels were measured by HPLC-MS/MS. Isoenzyme expressions were grouped according to their main physiological function (oxidative or reductive) and preferred substrate (androgen or estrogen). As expected, testicle was the main site for synthesis of testosterone and estradiol, and the liver the main organ oxidizing them to androstenedione and estrone. Overall oxidative capacity was 6.5-fold higher than the reductive, and estradiol synthesis and oxidation potential were higher than for testosterone. OE decreased serum androgens, and increased estrone, but not estradiol. This was due to decreased testicle ability to produce testosterone, because of smaller size and decreased 17betaHSDH3 expression, but also to lower availability of precursors. High estrone availability (from OE hydrolysis) does not translate into higher estradiol because of decreased testicle reductive 17betaHSDH expression and decreased aromatase. In consequence, we can assume that OE effects on androgens, and the hypothalamic-pituitary-gonadal axis are limited to testicles.
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PMID:Influence of oleoyl-estrone treatment on circulating testosterone. Role of 17beta-hydroxysteroid dehydrogenase isoenzymes. 1943 21