Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00627 (MAP)
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Uteroglobin was obtained from 5 day pregnant rabbits and purified to homogeneity by Sephadex G 75 and DEAE-cellulose chromatographies. Progesterone binding to uteroglobin was decreased by lyophilization and enhanced by SH-reducing agents. Dithiothreitol was more effective than dithioerythritol, and beta-mercaptoethanol was only active at 25 to 100 mM concentrations. SH-blocking agents (iodoacetate, iodoacetamide, phydroxymercuribenzoate and, dithiobisnitrobenzoic acid) inhibited binding. In the absence of SH-reducing agents only one in every 500 uteroglobin molecules bound the hormone, whereas under optimal conditions (20 mM dithiothreitol) one in every two molecules bound progesterone. There was no significant difference in equilibrium dissociation constants under these two conditions. Uteroglobin had a relatively high affinity for progesterone (KD=4.1 X 10(-7)M) but a threefold higher affinity for 5alpha-pregnane-3,20-dione (KD=1.3 X 10(-7)M). Estradiol was bound but non-specifically with a very low affinity, and its binding was not enhanced by SH-reducing agents. Hormonal specificity of binding to uteroglobin was different from that of binding to rabbit uterine progesterone receptor. Various synthetic progestagens (chlormadinone acetate, norethisterone, R5020) were bound to the latter but not to the former protein. Diethylstilbestrol had some affinity (15% of that of progesterone) for uteroglobin and no affinity for the progesterone receptor. Uteroglobin incubated in the presence or absence of cofactors (NADH and NADPH) with or without dithiothreitol did not metabolize progesterone.
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PMID:Interaction of uteroglobin with progesterone, 5alphapregnane-3,20-dione and estrogens. 1 Oct 93

Estradiol and testosterone both lowered endogenous liver glycogen and at 20-fold higher doses impaired triamcinolone acetonide mediated glyconeogenesis in adult adrenalectomized male rats. Neither steroid influenced liver tyrosine transaminase although tryptophan pyrrolase activity was depressed by testosterone. Progesterone increased liver tryptophan pyrrolase but did not influence other parameters. Cortexolone did not alter either of these processes whereas cortisol induced both enzymes and, at much higher dose levels, gluconeogenesis. Binding of 3H-triamcinolone acetonide to its cytoplasmic receptor in vitro was left unaffected in presence of 20-fold greater concentration of either sex steroid but almost totally abolished by cold, homologous molecules. Similar results were obtained by 3H-cortisol except that estradiol partially competed for 3H-cortisol binding sites even at 20-fold greater concentrations of cold estradiol. Separation on DEAE-cellulose-52 and Ultrogel 44 columns revealed binding of all steroids to macromolecules of comparable physicochemical properties although the ratios of binding to the various subpopulations of the receptor were a function of the steroid in question. These results are discussed in terms of sex steroid binding to different moieties of a complex, heterogeneous, polymorphic protein rather than inhibition of binding to the active configuration acquired in presence of an inducer.
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PMID:Search for antiglucocorticoid activity in rat liver in vivo. 4 49

Estradiol-benzoate (EB) injected into previously ovariectomized (OVX) rats, increased pituitary ATPase activity 69% over controls, within one hour of treatment. Twelve hours after injection, ATPase activity was not significantly different from controls. Progesterone [(P): 5mg/100gBW] administered in conjunction with EB elicited an analogous response. AT at time of EB and EB+P induced increments in pituitary ATPase activity, plasma LH levels were dramatically reduced to normal, intact diestrous control levels. Post-castrational elevations in FSH were also suppressed after one hour of treatment with EB, but not following EB+P administration. The results suggest that the inhibitory actions of EB and EB+P on post-castrational LH levels may be related to modulation by these steroids of pituitary membrane ATPase activity.
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PMID:Estrogen (EB) and EB + progesterone (P) induced changes in pituitary sodium, potassium adenosine triphosphatase activity (ATPase). 13 41

17 beta estradiol, progesterone, prostaglandin E and prostaglandin F2 alpha were determined in the plasma of mice at different times of pregnancy. Estradiol displays a preimplantation peak on day 4. Other peaks are visible at the end of the implantation period (day 6) and on day 10. Progesterone increases when implantation begins (day 5). Prostaglandins increase at the beginning of pregnancy and decrease temporarily before implantation. Other peaks are also apparent for prostaglandin E on days 5.5 and 11.
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PMID:[Development of estradiol, progesterone, and prostaglandins E and F2 alpha levels during pregnancy in mice]. 16 Feb 79

Medroxyprogesterone acetate (Provera) was administered orally during 2-4 days to women undergoing endometrial curettage during the follicular phase of the menstrual cycle. Estradiol (E2) receptor levels were estimated from the amounts of 2H-E2 tightly bound in nuclei after incubation of endometrial tissue with an excess of the labeled hormone. An average value (9 subjects) of 1.5 pmole E2/mg DNA +/- 0.7 (mean +1- SD) was found. This value is significantly lower than the average E2 receptor levels in proliferative endometrium of untreated subjects (3.2 +/- 1.3, n = 33) and equals the level observed in the early secretory phase (1.5 +/- 0.5, n = 5). These results indicate that one of the progestin effects on human endometrium is the reduction of E2 receptor levels.
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PMID:Effects of progestins on estradiol receptor levels in human endometrium. 16 81

In order to characterize the uterine progesterone-binding proteins of oestrogen-primed and unprimed, ovariectomized immature and adult golden hamsters, cytosols were incubated with [3H]progesterone and/or other steroids and analyzed by sucrose-glycerol density gradient ultracentrifugation. Progesterone-binding components with sedimentation coefficients of 7S and 4.5S were found in the uterine cytosols, but not in the cytosols from the hypothalamus, pituitary, diaphragm, or small intestine. Oestradiol-17beta markedly elevated the level of 7S uterine receptor and this increase appeared to be due to new receptor synthesis, since actinomycin D and cycloheximide blocked this response. Fifty to 100 mug of oestradiol-17beta per kg body weight was found to promote a maximum increase in the 7S macromolecular component. The 7S receptor showed a tendency to saturate at 1 X 10(-7) M [1,2-3H]progesterone, indicating limited capacity. At a molar ratio of 100:1, unlabeled progesterone competed effectively for 7S and 4,5S [3H]progesterone binding, whereas 5alpha-pregnane-3,20-dione, oestradiol-17beta and testosterone did not. Moreover, [1,2-3H]cortisol and [1,2-3H]corticosterone did not bind to the 7S receptor, implying steroid specificity. CI-628, a non-steroid oestrogen antagonist, completely prevented [6,7-3H]oestradiol-17beta binding to its 8.5S uterine cytosol receptor, but was entirely without effect on 7S and 4.5S [3H]progesterone binding. Pronase, but not DNase or RNase, abolished 7S and 4.5S progesterone binding, suggesting that the binders are at least in part protein. Protamine sulphate and p-hydroxymercuribenzoate also obliterated 7S binding, implying that this receptor may be an acidic protein which contains sulfhydryl groups that are necessary for progesterone binding.
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PMID:Oestrogen-inducible uterine progesterone receptors. characteristics in the ovariectomized immature and adult hamster. 17 Jul 71

Norethindrone (ENT), which is a representative in estrane series of progestogen, is not only strongly progestational but also estrogenic and in some cases, antiestrogenic. To understand progestational effect and antiestrogenic effect, the interactions of ENT on estrogen and progestogen receptors were studied in the uterine cytosol of white female rabbit. The 274,200 X G supernatant of uterine homogenate was used as cytosol. 3H-Estradiol, 3H-Progesterone, 3H-ENT or cold ENT were incubated with uterine cytosol at 4 degrees C for 2 hours. Results are as follows: 1. Sucrose gradient centrifugation [5 approximately 20% linear and 40,000 rpm (159,200 X G) for 16 hours at 4 degrees C]: ENT was bound to extrogen 8S receptor in immature rabbit uterus (Fig. 2 & 3), and to progestogen 8S receptor in estrogen primed rabbit uterus (Fig. 5). 2. Kinetic study, determined by dextran coated charcoal (0.001% dextran and 0.1% charcoal): (1) In the uterine cytosol of immature rabbit, 3H-estradiol-receptor binding was observed with Kd divide by 3.6 X 10-9 M and it was revealed that ENT was a competitive inhibitor to this binding with Ki divide by 2.6 X 10-6 M, as in Fig. 6. (2) 8S component, obtained by centrifugation of uterine cytosol (Fig. 1) in estrogen primed rabbit, binds 3H-progesterone with Kd divide by 8.1 X 10-10 M and Bm (maximal binding sites) divide by 5.0 X 10-8 M/mg of protein, and ENT was a competitive inhibitor in this binding with Ki divide by 2.3 X 10-9 M (FIG. 7 & 8). 3H-ENT-8S binding was demonstrated with Kd divide by 1.1 X 10-9 M and Bm divide by 8.7 X 10-8 M/mg of cytosol protein (Fig. 8). These results indicate: (a) ENT is bound to both estrogen and progestogen receptors in 8S macromolecules of uterine cytosol, (b) competitive inhibition of ENT to these bindings indicated that ENT is bound to these receptors at the steroid binding sites where estradiol and progesterone bind to, (c) ENT has much more affinity to progestogen receptor (Ki divide by 2.3 X 10-9 M) than to estrogen receptor (Ki divide 2.6 X 10-6 M), (d) while ENT is bound to progestogen and estrogen receptors at the same time, Bm of ENT (8.7 X 10-8 M/mg of cytosol protein) is more than Bm of progesterone (5.0 X 10-9 M/mg of cytosol protein), and Kd of ENT (1.1 X 10-9 M) was less than Ki of ENT (2.3 X 10-9 M) in the binding to progesterone-receptor. Biologically, while ENT is bound to progestogen -receptor with high affinity and to estrogen receptor with low affinity, ENT is actually progestational in low dose and antiestrogenic in high dose but the anti-estrogenicity seems to be incomplete in vivo as ENT may be metabolized to a potent estrogenic compound, ethinyl estradiol
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PMID:[Interaction of norethindrone on estrogen and progesterone receptors in the rabbit uterine cytosol (author's transl)]. 18 90

1 The in vitro action of oestradiol-17-beta (0.1, 1.0 and 10.0 mug/ml) and progesterone (0.1, 1.0 and 10.0 mug/ml) on the spontaneous activity of the portal veins in female rats at different stages of gestation was studied. 2 Progesterone caused the spontaneous mechanical activity in the rat portal vein to decrease in amplitude and increase in frequency. This action was dose-dependent and the sensitivity of the tissue decreased throughout pregnancy. 3 Oestradiol-17-beta had a biphasic effect on spontaneous mechanical activity in the rat portal vein. At 0.1 mug/ml the vessel was stimulated while a similar effect to progesterone occurred with higher concentrations. The tissue was more sensitive to oestradiol at 7 days of gestation than at either the 10-14 or 17-21 day periods of gestation. 4 These effects of oestradiol and progesterone were still seen after blockade of the beta-adrenoceptors. 5 Hydrocortisone (10 mug/ml) had no inhibitory effect on the spontaneous mechanical activity of the vein. 6 The veins from the 17-21 days pregnant animals showed a smaller amplitude of contraction than comparable non-pregnant females.
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PMID:The inhibitory action of oestradiol-17-beta and progesterone on venous smooth muscle. 23 98

Nine ovarian Sertoli-Leydig tumors, showing varying degrees of differentiation, one pure ovarian Sertoli cell tumor, and one poorly differentiated stromal tumor of the testis, were examined for the presence of testosterone, estradiol and progesterone with an indirect immunoperoxidase method on formalin fixed paraffin embedded tissue. Clinically all nine patients with Sertoli-Leydig tumors had evidence of increased androgen production, manifested by either hirsutism or virilization; elevated serum testosterone was found in all four patients in whom it was measured. The patients with the pure ovarian Sertoli cell and testicular tumors were asymptomatic except for the presence of a mass. Testosterone was identified in Leydig cells in nine instances, in Sertoli cells in six, and in poorly differentiated spindle cells resembling the mesenchyme of the embryonic gonad in two. Cells with vacuolated cytoplasm, both Sertoli and Leydig cells, though positive for lipid were consistently negative for testosterone. Estradiol was present in Leydig cells in nine instances, in Sertoli cells in five, and in primitive gonadal stomal cells in two. The pattern of distribution was similar to that of testosterone but the intensity of the reaction for estradiol was generally less than that for testosterone. Progesterone was identified in Sertoli cells in one instance and was weakly positive in Leydig cells in three instances. The presence of testosterone and estradiol in both Sertoli and Leydig cells as well as in primitive spindle cells resembling those found in the embryonic gonad suggests that the latter cell is the precursor for both Sertoli and Leydig cells.
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PMID:An immunohistological study of steroid localization in Sertoli-Leydig tumors of the ovary and testis. 36 Dec 11

The hamster ductus deferens cloned tumor cell line (DDT1) has been shown to contain both androgen and glucocorticoid binding activity. The androgen receptor binding site concentration is 1.07 x 10(-13) mol of testosterone/mg protein, and testosterone (T) binds with a Kd of 4.3 x 10(-10) M. Dihydrotestosterone (DHT) is also bound to the receptor with a Kd of 2.99 x 10(-10) M and the binding site concentration is 1.33 x 10(-13) mol/mg protein. The order of steroid binding affinity is DHT greater than T greater than Estradiol greater than Progesterone. Cortisol, dexamethasone, and triamcinolone acetonide do not inhibit the androgen binding in vivo or in vitro. In a cell free system antiandrogens inhibit the binding of DHT. The DDT1 cells have a separate receptor for cortisol which binds at saturation 3.44 x 10(-13) mol cortisol/mg protein and has a Kd of 4.54 x 10(-9) M. These studies provide evidence that these endocrine target cells contain specific high affinity receptors for more than one type of steroid. The glucocorticoid receptor may be important for maintaining essential undifferentiated functions while the DHT receptor gives the specific characteristics of sex hormone responsive tissues.
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PMID:The coexistence of androgen and glucocorticoid receptors in the DDT1 cloned cell line. 40 58


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