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)

Epididymal 5alpha reductase activity was found distitributed in the crude nuclear fraction (44 percent) and microsomal fraction (41 percent). Spermatozoa contaminating the nuclear preparation accounted for only 3 percent of its activity. There were no regional differences in the distribution of total 5alpha reductase activity. However, the nuclear enzyme was more active in caput than in other regions. Maximal activity was found at pH 6.2 and at 32 degrees C. Both enzymes had an absolute requirement of reduced dinucleotides. The microsomal preparation could only us NADPH while the nuclear enzyme could use NADPH and NADH. The apparent Km for the microsomal preparation was 0.62 +/- 0.05 X 10(-6)M and Vmax was 555 +/- 38 pmoles/mg protein/hour. The nuclear enzyme presented similar values. The reaction was not inhibited by accumulation of product in the medium, but other steroids such as progesterone, epitestosterone (17alpha-hydroxy-4-androsten-3-one) and 3-oxo-4-androstene-17beta-carboxylic acid were potent competitive inhibitors. The reaction was strongly inhibited by Hg, Zn and Cu. The properties of the epididymal reductase are similar to those of the prostatic enzyme.
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PMID:Partial characterization of epididymal 5 alpha reductase in the rat. 2 73

Progesterone, epitestosterone (4-androstene-17 alpha-ol-3-one, EpiT) and 4- androstene-3-one-17 beta-carboxylic acid (COOH), three known in vitro inhibitors of 5 alpha reductase, were injected daily for 30 days to male rats to study their effect on some parameters of epididymal function. Progesterone at the dose of 750 and 2000 micrograms/day decreased fertility by 59% and 50% respectively. EpiT at a dose of 1500 micrograms/day decreased fertility by 74%. These treatments did not change the sperm counts in the cauda epididymis. Treatment with COOH did not decrease fertility. Progesterone at 750 and 2000 micrograms/day and EpiT at 750 micrograms/day decreased the weight of the epididymis, prostate and seminal vesicles. None of the compounds tested produced variations in body weight or in the weight of liver and testis. The 5 alpha reductase activity of epididymis, testis and liver was diminished by progesterone treatment, while EpiT decreased only that of testis and liver.
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PMID:Effect of in vivo administration of 5 alpha reductase inhibitors on epididymal function. 26 19

Two siblings with 46,XY male pseudohermapthroditism were demonstrated to have the phenotype characteristic of 5 alpha-reductase deficiency, namely normal testes and male Wolffian duct derivatives (epididymis, vas deferens, and seminal vesicle) terminating in a blind-ending vagina. Clitoromegaly was present at birth and increased further at the time of expected puberty. The diagnosis of 5 alpha-reductase deficiency was confirmed by demonstration of male levels of testosterone and testosterone precursors before and after hCG administration, elevated plasma testosterone to dihydrotestosterone and urinary etiocholanolone to androsterone ratios, and by in vitro studies indicating 5 alpha-reductase enzyme deficiency in the epididymis of one patient. Studies of control and mutant epididymal microsomes indicated that a single enzyme is responsible in the normal person for the 5 alpha-reduction of testosterone and cortisol (and probably other delta 4-3-ketosteroids as well) and that 5 alpha-reductase activity is undetectable for all substrates examined in the mutant. This finding explains why the formation of 5 alpha-reduced glucocorticoids is also defective in the disorder.
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PMID:Clinical, endocrinological, and enzymatic characterization of two patients with 5 alpha-reductase deficiency: evidence that a single enzyme is responsible for the 5 alpha-reduction of cortisol and testosterone. 26 18

The effects of unilateral orchidectomy on the adult rat epidiymal testosterone metabolizing enzymes, delta 4-5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase, are investigated. Five weeks following unilateral orchidectomy, it is found that the activity of 3 alpha-hydroxysteroid dehydrogenase per organ is not altered, whereas delta 4-5 alpha-reductase activity decreased by more than 80% on the side of the orchidectomy. Neither accessory sex tissue weights, ventral prostate and seminal vesicles, nor the concentration of circulating testosterone, luteinizing hormone, follicle-stimulating hormone, or prolactin is altered by unilateral orchidectomy. These data indicate that (1) epididymal 3 alpha-hydroxysteroid dehydrogenase activity can be maintained by circulating androgens and that (2) the major factor regulating delta 4-5 alpha-reductase activity is not a substance secreted by the testes into the peripheral circulation. It is suggested that a substance directly secreted into the epididymis by the testis regulates epididymal delta 4-5 alpha-reductase activity.
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PMID:Effects of unilateral orchidectomy on rat epididymal delta 4-5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase. 51 41

Studies were performed to compare the effects of 5 alpha-reductase inhibition and antiandrogen receptor blockade on differentiation of male internal and external genital structures and prostate in the rat. Dose-response studies were performed on male rats treated in utero during the period of sexual differentiation with either the potent 5 alpha-reductase inhibitor finasteride or the antiandrogen flutamide. The treated animals were raised to adulthood and killed, and genital structures were evaluated. Treatment with the 5 alpha-reductase inhibitor finasteride at a dose of 25 mg/kg.day resulted in significant feminization of the external genitalia. There was no further feminization of the genitalia at doses up to 300 mg/kg.day. Wolffian ductal differentiation occurred at all doses evaluated. Seminal vesicle weight, however, significantly decreased at 25 mg/kg.day, but without a further decrease at higher doses of the 5 alpha-reductase inhibitor. Vas deferens and epididymal weights were unchanged at all doses evaluated. There was a significant decrease in prostate size at 25 and 50 mg/kg.day, with no further decrease at higher doses. In flutamide-treated animals, complete feminization of the genitalia occurred at 24 mg/kg.day in all animals. At 18 mg/kg.day, Wolffian ductal differentiation occurred, but seminal vesicle weight was decreased. At dosages of 100, 200, and 300 mg/kg.day flutamide, the vas deferens was absent unilaterally or bilaterally, with small remnants of epididymal head and tail present. At dosages of 24 mg/kg.day and above, the prostate was absent. Studies with the 5 alpha-reductase inhibitor finasteride demonstrate the dependency of prostate and male external genital differentiation on dihydrotestosterone (DHT). However, unlike androgen receptor blockade with flutamide, finasteride did not totally abolish prostate differentiation or completely feminize the external genitalia, despite increasingly higher doses. Since there is no evidence of multiple 5 alpha-reductase isoenzymes to date in the rat, these results suggest that testosterone (T) can compensate for DHT to some degree at the level of the androgen receptor. Wolffian differentiation, however, was not affected by inhibition of DHT, demonstrating its T dependency, but seminal vesicle growth was impaired. Thus, inhibition of 5 alpha-reductase activity limits seminal growth potential in adulthood. Studies with the antiandrogen flutamide show that at doses significantly above that required to completely block prostate differentiation and cause genital feminization, Wolffian ductal differentiation is significantly impaired. Thus, higher doses of flutamide are needed to block the paracrine effect of T on the Wolffian ducts.
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PMID:Comparison of the effects of the 5 alpha-reductase inhibitor finasteride and the antiandrogen flutamide on prostate and genital differentiation: dose-response studies. 132 52

The regulation of epididymal 5 alpha-reductase mRNA is multifactorial and segment-specific. To further investigate the regulation of the message for the enzyme, the expression of 5 alpha-reductase mRNA in the rat epididymis was studied as a function of postnatal development. Developmental changes in 5 alpha-reductase mRNA concentrations were assessed by probing Northern blots with the full-length cDNA for rat steroid 5 alpha-reductase. In the first experiment the effect of postnatal age on 5 alpha-reductase mRNA concentrations in the caput-corpus and cauda epididymides was studied. Male rats, taken at 1-week intervals between the ages of 7-91 days, were used. In both epididymal regions, the mRNA for 5 alpha-reductase was present at all ages examined; it appeared in the immature animal at least 2 weeks before detectable 5 alpha-reductase enzyme activity. In the caput-corpus epididymidis, mRNA levels for 5 alpha-reductase decreased by half between postnatal days 7 and 21, rose 5-fold by day 56, and then remained constant through day 91. No change with postnatal age, however, was observed in the cauda epididymidis. In the second experiment, the longitudinal distribution of 5 alpha-reductase mRNA on postnatal days 21, 42, 49, 56, 77, and 91 was studied. The mRNA levels for 5 alpha-reductase increased remarkably, by 6- to 7-fold, in the initial segment of the caput epididymidis between postnatal days 21 and 42 and stayed constant thereafter. However, no significant change comparable to that found in the initial segment was observed in the adjacent proximal caput region or in any of the other epididymal segments. Thus, the 5-fold rise in 5 alpha-reductase mRNA concentrations that occurred in the caput-corpus epididymidis in the first experiment can be attributed solely to changes in the initial segment. We conclude that steady state concentrations of epididymal 5 alpha-reductase mRNA vary dramatically at different postnatal ages and are highly specific with respect to epididymal segment.
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PMID:Expression of 4-ene steroid 5 alpha-reductase messenger ribonucleic acid in the rat epididymis during postnatal development. 150 81

The effect of several synthetic steroids belonging either to the 4-aza-3-oxo-steroid family or to androstene and androstane derivatives was investigated "in vitro" on the epididymal as well as prostatic 5 alpha-reductase activity. For this purpose rat caput epididymis and prostate were incubated with the different steroidal compounds at molar concentrations of 10(-7), 10(-6), and 10(-5) in the presence of labelled testosterone as substrate. The steroids 4-MA (17 beta, N,N-diethyl-carbamoyl-4-aza-5 alpha-androstan-3-one) and 4-OH-A (4-hydroxy-androstenedione), already known to be effective 5 alpha-reductase inhibitors at the level of the prostate, have been used as reference molecules. The 5 alpha-reductase activity was evaluated by measuring pg of dihydrotestosterone (DHT) formed in 2 h of incubation by mg of tissue. The steroids A, B, C, F, G and I inhibit the formation of DHT in the rat epididymis although to different extents; they are also equally effective on the formation of DHT in the rat prostate. The steroids D, E, H and L are devoid of any inhibitory property on the formation of DHT in both the rat epididymis and prostate. The most interesting results were obtained with compound M which exhibits a dose-dependent and significant inhibitory effect on the formation of DHT in the epididymis, but it is inactive at the level of the prostate. These findings suggest that it is possible (a) to selectively interfere with the 5 alpha-reductase of the epididymis without affecting that present in the prostate, and (b) consequently to envisage new ways to regulate male fertility.
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PMID:Selective inhibition of the 5 alpha-reductase of the rat epididymis. 161 80

Oral administration of 80 mg/kg/day of finasteride, a potent specific inhibitor of 5 alpha-reductase, to sexually mature male Sprague-Dawley rats for 24 to 38 weeks caused an approximate 30% to 40% decrease in fertility. There were no effects on mating indices or implants per pregnant female. From the mating trials, a selected group of treated males with poor reproductive performance was compared to a selected group of control males with good reproductive performance. Observed matings showed no qualitative effects on mating behavior or ejaculation. However, finasteride-treated males did not form or formed small and improperly positioned copulatory plugs, which are required in rats to transport sperm into the uterus. Intrauterine insemination of epididymal sperm from males that were nonfertile by natural mating resulted in similar numbers of embryos and unfertilized oocytes recovered from controls and finasteride-treated males, confirming that there was no effect of finasteride on the ability of sperm to fertilize. Decreased fertility of finasteride-treated males was due to failure to form copulatory plugs and is related to decreased weight of seminal vesicles and prostate, an expected pharmacologic effect. Testes weight was unaffected. Decreased fertility in male rats after finasteride administration is considered a species specific effect. The mechanism of the decrease in rats is not likely to be relevant to species that do not form copulatory plugs.
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PMID:Decreased fertility in male rats administered the 5 alpha-reductase inhibitor, finasteride, is due to deficits in copulatory plug formation. 166 58

Inhibition of androgen action by flutamide, a nonsteroidal antiandrogen, blocked testicular descent in 40% of the testes exposed to this agent continuously from gestational day 13 through postpartal day 28. By contrast, only 11% of the testes failed to descend when blocked by 5 alpha-reductase inhibitors during the same period. Flutamide administration over narrower time intervals (gestational day 13-15, 16-17, or 18-19) revealed maximal interference with testicular descent after androgen inhibition during gestational days 16-17. No significant differences in testicular or epididymal weights were evident between descended and undescended testes; furthermore, no correlation was detected between the presence of epididymal abnormalities and testicular descent. These findings indicate that androgen inhibition during a brief period of embryonic development can block testicular descent. The mechanism through which this inhibition occurs remains to be elucidated.
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PMID:Time-specific androgen blockade with flutamide inhibits testicular descent in the rat. 167 99

Male mouse urogenital ridges (URs) at 15.5 days of gestation (vaginal plug = day 0) containing Wolffian (WDs) and Mullerian ducts were cultured for 4 days with or without gonads in serum-free medium (1:1 mixture of Dulbecco's modified Eagle's medium and Ham's F-12 supplemented with insulin, transferrin, cholera toxin, epidermal growth factor, and BSA). URs without gonads were grown in serum-free medium with testosterone (T, 10(-7) M), 5 alpha-dihydrotestosterone (DHT, 10(-8) M), T (10(-7) M) plus cyproterone acetate (antiandrogen, 10(-5) M), or T (10(-8) M) plus 390 MSD (17 beta-N, N-diisopropylcarbamoyl-4-aza-5 alpha- androstan-3-one, an inhibitor of 5 alpha-reductase, 10(-5) M). After 4 days of culture the number of epididymal curvatures that appeared in the upper portion of WDs were quantified. DNA content of URs grown in serum-free medium was also measured. Both T and DHT increased DNA contents in a dose- (T = 10(-8) to 10(-10) M, DHT = 10(-9) to 10(-11) M) and time-dependent manner. DHT was approximately 10-fold more effective than T in eliciting epididymal coiling and increasing DNA content of URs. The effects of T or DHT were mimicked by coculture with fetal testes. Epididymal coiling and an increase in DNA content occurred in URs grown in the presence of T plus 390 MSD. By contrast, URs cultured without androgens or with T plus cyproterone acetate failed to undergo epididymal coiling and to increase DNA content. The conversion rate per mg protein of [1 beta, 2 beta-3H]T into [3H]DHT was 0.30-fold lower in 15.5 day URs cultured over a 4-day period in comparison to urogenital sinuses whose development is known to be dependent upon DHT. These data suggest that T is an important hormone in the development of the upper portion of WDs, although it is not possible to exclude a role for DHT in the development of the epididymis.
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PMID:In vitro androgen-induced growth and morphogenesis of the Wolffian duct within urogenital ridge. 182 79


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