Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enzyme steroid 5 alpha-reductase (EC 1.3.1.22) catalyzes the conversion of testosterone to its more potent form, dihydrotestosterone (DHT), in many androgen-sensitive target tissues. In the epididymis, the 5 alpha-reduced metabolites of testosterone, DHT and 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-diol), are considered the primary regulators of epididymal structure and function. Two rat 5 alpha-reductase transcripts, designated types 1 and 2, have been identified. Our laboratory has previously characterized the endocrine and developmental regulation of the 5 alpha-reductase type 1 mRNA in the rat epididymis. However, regulation of the type 2 mRNA has not been investigated. Thus, we undertook to characterize the longitudinal distribution of the steady state 5 alpha-reductase type 2 mRNA as well as the effects of development and of unilateral efferent duct ligation on its expression in the rat epididymis. To contrast the regulation of the type 2 5 alpha-reductase isozyme mRNAs in the rat epididymis, these data have been compared with those previously obtained for the type 1 mRNA and enzyme activity. An analysis of the longitudinal distribution of the type 2 transcript along the epididymis revealed that its mRNA was expressed predominantly in the proximal caput region of the tissue. This regional distribution pattern differed markedly from the patterns previously described for the type 1 mRNA and enzyme activity. Surprisingly, a segment-by-segment analysis showed that epididymal 5 alpha-reductase type 2 mRNA levels were not altered as a function of increasing postnatal age. Again, this result was in marked contrast to the important changes in 5 alpha-reductase type 1 mRNA and enzyme activity that have been reported to occur during puberty in the rat. In the final experiment, the effect of unilateral efferent duct ligation revealed that 5 alpha-reductase type 2 mRNA levels increased in the initial segment of the ligated side but remained unchanged in the rest of the tissue; this was in marked contrast to the dramatic decrease (>60%) in type 1 mRNA levels observed specifically in the initial segment of the epididymis. Taken together, these experiments demonstrate that 5 alpha-reductase type 1 and type 2 mRNAs are differentially regulated in the rat epididymis. Moreover, this is the first report of a tissue in which the mRNAs for the steroid 5 alpha-reductase isozymes are regulated differently.
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PMID:The mRNAs for the steroid 5 alpha-reductase isozymes, types 1 and 2, are differentially regulated in the rat epididymis. 883 38

Fertility and reproduction studies were conducted in rats with the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, atorvastatin. Male rats received vehicle (0.5% methylcellulose) or atorvastatin at 20, 100, or 175 mg/kg by oral gavage for 11 weeks prior to mating with untreated females; treatment continued throughout mating and until necropsy on Day 115. An untreated control group of males was also included in the same procedures. Dose-related body weight gain suppressions of 17 and 25%, and food consumption suppressions of 7 and 16%, occurred during the 11-week premating treatment period at 100 and 175 mg/kg, respectively, compared with vehicle controls. There were no treatment-related effects on testes, epididymides, or accessory organs weights, testicular or epididymal sperm counts, sperm motility, or sperm morphology during Week 15 of treatment. Plasma drug concentrations during Week 15 increased with dose to a Cmax of 1820 +/- 1020 ng eq/ml at 175 mg/kg. There were no effects on copulation or fertility indices, number of days to mating, or female reproductive parameters (number of implants, live fetuses, or pre- and postimplantation loss). In the female fertility study, female rats received vehicle (0.5% methylcellulose) or atorvastatin at 20, 100, or 225 mg/kg by oral gavage for 2 weeks prior to mating with untreated males; treatment continued throughout mating and until Gestation Day 7. Sperm-positive females were sacrificed on presumed Gestation Day 13 to 15 for evaluation of reproductive parameters. Body weight gain in atorvastatin groups was comparable to controls during the premating period, but was suppressed by 35% at 225 mg/kg during the treatment period of gestation (Days 0-8), and was significantly increased at 225 mg/ kg during the posttreatment period of gestation (Days 8-13). Plasma drug concentrations on premating treatment Day 14 increased with dose to a Cmax of 7030 +/- 3680 ng eq/ml at 225 mg/ kg. The mean number of estrous cycles, copulation and fertility indices, number of days to mating, and number of viable litters were comparable between groups. In addition, term sacrifice parameters (number of corpora lutea, implants, live fetuses, pre- and postimplantation loss) were not significantly different between groups. Thus, these studies demonstrate no adverse effects of atorvastatin on fertility and reproduction in rats at doses up to 175 and 225 mg/kg in males and females, respectively, and 20 mg/kg was a no-effect dose.
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PMID:Fertility and general reproduction studies in rats with the HMG-CoA reductase inhibitor, atorvastatin. 892 32

The difference between in vivo and in vitro inhibitory effects on epididymal 5 alpha-reductase was investigated by using epididymides obtained from patients treated with chlormadinone acetate (6-chloro-3,20-dioxo-4,6-pregnadien-17-yl acetate, CMA) or ethinylestradiol (17 alpha-ethynyl-1,3,5(10)-estratriene-3,17 beta-diol, EE2). In the in vitro study CMA exhibited competitive inhibition, whereas EE2 was a noncompetitive inhibitor of human epididymal 5 alpha-reductase. Their in vitro inhibitory effects were weak compared with the effect of finasteride ((-)-N-tert-butyl-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta carboxamide), a steroidal 5 alpha-reductase inhibitor. The Ki values of CMA, EE2, and finasteride were 1.4 x 10(-5) M, 1.5 x 10(-5) M, and 1.3 x 10(-9) M, respectively. Despite their weak in vitro inhibitory potency, CMA and EE2 strongly inhibited testosterone 5 alpha-reductase in vivo. There were regional differences in inhibitions by CMA and EE2 on human epididymal 5 alpha-reductase activity depending on the site of the epididymis; the efferent ductules, the head, the body or the tail. In vivo administration of CMA reduced epididymal 5 alpha-reductase activity by 49.7% to 89.4%. In vivo administration of EE2 reduced epididymal 5 alpha-reductase activity by 82.7% to 96.3%. The apparent Km values for the enzyme in patients treated with CMA or EE2 and untreated patients did not differ significantly. The Vmax values were significantly decreased in treated patients. These findings suggest that the marked in vivo inhibition of 5 alpha-reductase induced by CMA and EE2 was not related to the direct action of these compounds, but resulted from a reduction in the amount of the enzyme.
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PMID:Effects of chlormadinone acetate and ethinylestradiol treatment on epididymal 5 alpha-reductase activities in patients with prostate cancer. 915 25

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to impair reproductive function of males in animal models, possibly due to a reduction in serum androgen levels. Thus, TCDD may alter the testosterone biosynthetic pathway in the testis or the conversion of testosterone to 5alpha-dihydrotestosterone (DHT) in androgen target tissues. Pregnant Sprague Dawley rats were gavaged with TCDD (0, 0.2 or 1.0 microg/kg) on day 15 of gestation only. TCDD caused a reduction in the body weight gain of the dams in both dose groups and a significant reduction in litter size in the higher dose group. Litters delivered normally and TCDD exposed male offspring grew at the same rate as controls. Males were sacrificed at 15, 30, 45, 60, 90 and 120 d of age. Steroidogenic enzyme activities were determined in testicular microsomes and androgen target tissue nuclear fractions. Serum androgens were measured by radioimmunoassay (RIA). At 30 d of age, rats exposed to 1.0 microg/kg TCDD exhibited lower 17-hydroxylase activity (P < 0.05) and lower caput-corpus epididymal weights (P < 0.05). At 45 d of age, the same treatment resulted in testicular 3beta-HSD, 17beta-HSD and 5alpha-reductase activities that were significantly greater (P < 0.05) but, conversely, serum androgens were one quarter the values evident in controls (P < 0.05). At the other ages, no differences were observed in serum androgens and, with the exception of lower 17beta-HSD activity at 90 d of age (P < 0.05), no other differences in testicular steroidogenic enzyme activities were found. 5Alpha-reductase activities in the androgen target tissues were also unchanged. Histological examination of testes showed that the spermatogenic profile was identical to controls at all ages.
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PMID:Effects of in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on serum androgens and steroidogenic enzyme activities in the male rat reproductive tract. 988 92

During epididymal transit, mammalian spermatozoa acquire new surface proteins that are necessary for gamete interaction. We have previously described a 34-kDa human epididymal sperm protein, P34H, that has been shown to be involved in sperm-zona pellucida interaction. In the present study, we report the cloning and characterization of the full-length complementary DNA encoding human P34H. The predicted amino acid sequence revealed 65% identity with P26h, the hamster counterpart of the P34H. The deduced P34H amino acid sequence revealed a 71% similarity with a pig lung tetrameric carbonyl reductase, a member of the short chain dehydrogenase/ reductase family proteins. Northern blot analysis revealed that P34H messenger RNA (mRNA) was highly expressed in the human epididymis, principally in the corpus region. A single 912-bp P34H transcript was detected. In situ hybridization experiments showed that the P34H mRNA was predominantly expressed in the proximal and distal sections of the corpus epididymidis. The staining was restricted to the principal cells of the epididymal epithelium. The localization of P34H mRNA was in agreement with the appearance of P34H protein along the male reproductive tract. Western blot analysis revealed that recombinant P34H expressed by a yeast expression system, is antigenically related to the native P34H sperm protein. Based on its pattern of expression and its function in one of the key steps leading to fertilization, P34H can be considered as a marker of epididymal sperm maturation in humans.
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PMID:P34H sperm protein is preferentially expressed by the human corpus epididymidis. 1038 29

Normal epididymal function is regulated by androgens and testicular factors. Our studies have been directed towards identifying testicular factors that regulate the function of the initial segment and the mechanisms by which this is achieved. The initial segment appears to be critical for normal sperm maturation in view of recent gene knock-out studies. Previous and ongoing studies from this and other laboratories have shown that the expression of several genes including proenkephalin, cystatin-related epididymal specific (CRES), 5 alpha-reductase and gamma-glutamyl transpeptidase (GGT) within the initial segment is highly dependent upon the presence of testicular factors. A lumicrine mechanism of regulation of these genes is proposed. The regulation of gamma-glutamyl transpeptidase (GGT) is described as a model enzyme for studying the role and identification of testicular factors. GGT appears to play an important role in the protection of spermatozoa from oxidative stress. Multiple GGT mRNAs (II-IV) are expressed within the epididymis, but GGT mRNA IV is the only form that is highly expressed in the initial segment, especially within zone 1A, and is regulated by testicular factors. Testicular factors control this transcript by regulating both its rate of transcription and its stability. Evidence is presented to suggest that basic fibroblast growth factor (bFGF) is a candidate testicular factor that regulates GGT activity in the epididymis. Basic FGF may regulate gene expression in the epididymis via the ras-raf-MAPK second messenger pathway and by members of the Ets transcription family.
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PMID:Testicular regulation of epididymal gene expression. 1064 65

Sperm analyses are often incorporated into reproductive toxicity studies in rats. Due to the relative ease of collecting multiple samples throughout a study, semen analysis in non-rodents such as dogs offers the opportunity to assess potential development of functional effects of compounds on male reproduction over time. In the present study, semen parameters were evaluated in beagle dogs during and at termination of a chronic toxicity study with the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, atorvastatin. Male dogs received 0, 10, 40, or 120 mg/kg orally in gelatin capsules for up to 104 weeks (n = 10/group). After 52 weeks of dosing, 3 dogs/group were euthanized, and 2/group were withdrawn from treatment for a 12-week reversal period and euthanized at Week 64. The remaining 5/group continued treatment until Week 104. Semen was collected from all animals for 3 consecutive weeks prior to termination of the 52-week animals (Weeks 50, 51, 52) for analysis of sperm parameters, using manual methods of evaluation. Semen was collected from the remaining animals at Weeks 64, 78, 91, and 104, and was analyzed. At necropsy, testes, epididymides, and prostates were weighed and evaluated histologically, and epididymal sperm counts were determined. Serum cholesterol was decreased 25--60% at all doses during the study. There were no drug-related differences in semen volume and color, total sperm count, and sperm concentration, morphology, progressiveness, and percent motility during treatment with atorvastatin. There were also no effects on reproductive organ weights or histopathology, and no effects on epididymal sperm count. Thus, incorporation of semen analyses into this study allowed the evaluation of potential male reproductive effects in dogs at multiple time points during the study. Statistical power calculations demonstrated acceptable statistical power (> 80%) for semen sperm count, concentration, morphology, and motility with group sizes of 8--10 animals, and for semen sperm count and concentration or epididymal sperm count with group sizes of 3--5 animals, using the methodology described in this paper.
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PMID:Repeated analysis of semen parameters in beagle dogs during a 2-year study with the HMG-CoA reductase inhibitor, atorvastatin. 1129 83

It is well established that congenital hypothyroidism leads to male infertility. However, there is a dearth of information on foetal-onset hypothyroidism-induced changes in the epididymis. With regard to transient hypothyroidism, the existing literature deals mainly with the testis. However, it is not known whether there is any corresponding alteration in epididymal morphology and physiology under such a condition. The present study is therefore aimed at understanding the impact of persistent and transient hypothyroidism on the concentration of epididymal sex steroids, as they play a vital role in maintaining the normal structure and function of the epididymis. Normal rats of 90 days of age served as controls (Group I). Hypothyroidism was induced by using pregnant/lactating mothers and post-weaning rats to 0.05% (w/v) methimazole (MMI) in the drinking water. Group II were subjected to persistent hypothyroidism from day 9 of post-coitum (pc) to 90 days. Group III rats were subjected to transient hypothyroidism from day 9 day pc to day 1 post-partum (pp), 21 pp or 35 pp (IIIa, b and c, respectively) and group IV rats were given simultaneous T3 supplementation (3 microg/100 g body wt./day i.m.) with MMI from day 9 pc to day 1 pp; 21 pp and 35 pp (Group IVa, b and c). Animals from all groups were killed on day 90 pp. Serum thyroid stimulating hormone (TSH) and thyroid hormones confirmed euthyroidism in group I, IIIa, b and c and IVa, b and c rats and hypothyroidism in group II rats. Caput and cauda epididymal concentration of testosterone, dihydrotestosterone (DHT), estradiol (E2) and androgen binding protein (ABP) markedly decreased in group II rats. While the concentration of testosterone, E2 and ABP increased in group III rats, that of DHT remained unaltered. However, group IV rats maintained normal concentration of the sex steroid and ABP. The activity of 5-alpha-reductase in the epididymis of all the groups followed the same trend as that of the concentration of epididymal DHT. From the present data it is evident that persistent hypothyroidism diminishes the bioavailability of androgens and oestrogens, while transient hypothyroidism enhances the same, indicating the importance of euthyroidism during foetal and neonatal period towards the maintenance of optimal hormonal status in the epididymis required for its maturation.
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PMID:Impact of foetal-onset hypothyroidism on the epididymis of mature rats. 1203 Oct 41

Lucigenin-dependent chemiluminescence and WST-1 reduction can be detected following addition of NADPH to many cell types, including rat epididymal sperm suspensions. Although many reports suggest that such a phenomenon is due to reactive oxygen species production, other probes-such as MCLA and luminol-that are capable of detecting reactive oxygen metabolites do not produce a chemiluminescent signal in this model system. Our aim was to purify and identify the enzyme catalyzing the NADPH-dependent lucigenin and WST-1 reduction from rat epididymal spermatozoa preparations. Here, we show the identity of this enzyme as cytochrome P450-reductase. In support of this, a homogenous preparation of this protein was capable of reducing lucigenin and WST-1 in the presence of NADPH. Moreover, COS-7 cells overexpressing cytochrome P450-reductase displayed a 3-fold increase in the aforementioned activity compared with mock-transfected cells. Immunolocalization studies and biochemical analysis suggest that the majority of the NADPH-lucigenin activity is localized to the epithelial cells present within the epididymis. These results emphasize the importance of the direct NADPH-dependent reduction of superoxide-sensitive probes by cytochrome P450-reductase even though this enzyme does not, on its own accord, produce reactive oxygen species.
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PMID:Identification of cytochrome P450-reductase as the enzyme responsible for NADPH-dependent lucigenin and tetrazolium salt reduction in rat epididymal sperm preparations. 1503 Nov 43

We have previously identified a 34 kDa protein (P34H) on the human sperm surface covering the acrosome. Using the hamster, we have also described a sperm protein, P26h, which is acquired by spermatozoa during epididymal transit. Both P34H and P26h belong to the carbonyl reductase family. Using molecular tools derived from P34H, we searched in the hamster epididymis for another protein related to the human sperm protein. Cloning and sequencing of P31h cDNA revealed 100% homology with the kidney DCXR (Dicarbonyl/L-Xylulose reductase). Northern Blot experiments revealed a single mRNA that was more expressed in the caput than in the corpus and cauda segment of adult epididymides. In situ hybridization was performed on sexually mature hamsters showing that the mRNA was localized in the principal cells throughout the epididymis. Using an anti-P34H antibody we have identified a P34H related protein named P31h (for 31 kDa). This protein showed 2D-electrophoretic behavior different from P26h and was detectable all along the epididymis (caput, corpus, and cauda) by Western Blot analysis. Immunohistochemistry techniques showed that P31h was localized in the perinuclear region of the principal cells of the epididymal epithelium within the three sections, both in sexually mature and immature animals. Results are discussed with regards to the potential function of DCXR in the epididymis.
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PMID:P26h and dicarbonyl/L-xylulose reductase are two distinct proteins present in the hamster epididymis. 1529 14


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