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Query: UNIPROT:P06889 (Mol)
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Monooxygenases in the cytochrome P450 IIIA subfamily are induced by a number of their xenobiotic substrates and by testosterone, an endobiotic substrate of importance in their regulation. 17 alpha-Ethinylestradiol (EE) is also metabolized by these enzymes and in this study Dark Agouti rats were used to examine the effects of subcutaneous implantation of controlled release silastic capsules containing EE to determine if this steroid also induces these enzymes. Data were compared with results obtained from equivalent groups of animals implanted with capsules containing testosterone propionate (TP). Liver microsomes prepared from male and female rats were used to identify intrinsic gender differences in the monooxygenases studied and gender differences in the responses to the implanted steroids were also determined. Effects due to imprinting of growth hormone secretion patterns were controlled by using male and female birth gonadectomized animals. Results obtained from groups with blank implants showed there were no effects due to the silastic implant material itself on the monooxygenases studied. The specific activities of erythromycin N-demethylation in liver microsomes of both EE and TP implanted male and female birth gonadectomized animals were enhanced relative to corresponding blank implanted controls consistent with both steroids having an effect to induce activity attributable to cytochrome P450 IIIA isoforms. Immunoinhibition studies using microsomes from EE treated female rats with erythromycin as substrate provided further evidence for this steroid having this induction effect. The specific activity of ethylmorphine N-demethylation was however not increased in microsomes prepared from the EE implanted female animals and was decreased in the corresponding male preparations. These findings distinguished the response to this steroid from that to TP and suggested induction by this estrogen of an isoform(s) having a more limited range of substrates than has characteristically been found in this subfamily. EE treatment also caused an increase in diazepam C3 hydroxylase consistent with an effect to induce P450 IIIA activity but this was found only in microsomes from birth gonadectomized female animals. This was in contrast to the effect of TP treatment which produced increases in this monooxygenase in both male and female animals. Another gender specific effect of EE was a striking decrease in morphine N-demethylase activity seen only in birth gonadectomized male rats. This again contrasted with the effect of TP which caused a marked increase in this activity in liver microsomes of both male and female birth gonadectomized animals consistent with the proposal that testosterone is important in the regulation of this activity.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1991 Nov
PMID:Effects of ethinylestradiol and testosterone implants on hepatic microsomal cytochrome P450 monooxygenases of birth gonadectomized male and female Dark Agouti rats. 195 10

A number of different progestogens, levonorgestrel (LNG), norethisterone (NET), gestodene (GSD), desogestrel (DG) and norgestimate (NORG) are used in combination with the oestrogen ethinyloestradiol (EE2) in oral contraceptive steroid preparations. All the progestogens are acetylenic steroids and previous studies have indicated the potential of acetylenic steroids to cause mechanism-based or "suicide" inactivation of cytochrome P-450. We have compared the effects of the different progestogens on EE2 2-hydroxylation (a reaction catalyzed by enzymes from the P-450IIC, P-450IIIA and P-450IIE gene families) and also the oxidative metabolism of other drug substrates (cyclosporin, diazepam, tolbutamide) by human liver microsomes. On coincubation with EE2 as substrate, GSD, 3-keto desogestrel (3-KD, the active metabolite of desogestrel) and LNG produced some concentration-dependent inhibition of EE2 2-hydroxylation (maximum 32% inhibition at 100 microM 3-keto desogestrel). Ki values determined for GSD and 3-KD were 98.5 +/- 12.3 and 93.2 +/- 10.3 microM (mean +/- SD; n = 4), respectively. Preincubation of progestogens in a small volume (50 microliters) incubation for 30 min in the presence of an NADPH-generating system enhanced the inhibitory potential of all the steroids (at 100 microM, inhibition was for GSD 39%, 3-KD 46%, LNG 46%, NET 51% and NORG 43%). Inhibitory effects were therefore comparable and also similar to the macrolide antibiotic troleandomycin. The most marked inhibition seen was of diazepam N-demethylation and hydroxylation by GSD (71 and 57%, respectively) and 3-KD (62 and 50%, respectively). In preincubation studies involving cyclosporin as the substrate, the order of inhibitory potency was GSD greater than 3-KD greater than NET greater than LNG for production of both metabolite M17 and M21. The results of the study indicate that all the progestogens in common use have the propensity to inhibit a number of oxidative pathways but there is little evidence for one progestogen being more markedly inhibitory than others.
J Steroid Biochem Mol Biol 1991 Feb
PMID:Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes. 200 43

Sex hormones have an effect on various immune responses but the mechanisms of action are unknown. One of these mechanisms might be a modification of expression of major histocompatibility complex (MHC) antigens in blood leucocytes. Estradiol-induced variations of the expression of guinea pig blood leukocytes MHC antigens (GPL-A) was studied. Class I and class II MHC antigens were detected by a sensitive rosetting method using specific alloimmune sera (AIS) and staphylococcal protein A-coated sheep red blood cells (SPA-SRBC) and evaluated by counting the number of bound SPA-SRBC per 100 cells. MHC antigens decreased after estrogen treatment. Estradiol modifies the expression of GPL-A antigens on the mononuclear cells including the Kurloff cells, which are involved in immunity or in a natural killer effect, but did not affect the expression of polymorphonuclear cells, ones which are not involved in immunity.
J Steroid Biochem Mol Biol 1991 Jun
PMID:17 beta estradiol affects the expression of guinea pig blood leukocyte MHC antigens. 206 84

Seven estradiol (E2) derivatives with an alkynylamide side chain at the 17 alpha position were synthesized starting from ethynylestradiol (EE2). The main chemical step was the coupling reaction of the acetylide ion of EE2 with carbon dioxide, glutaric anhydride or bromoalkyl ortho ester. The synthesis of these compounds is fast (3-6 steps according to the compound) and is easily achieved with good yield. Five compounds with different side chain lengths were evaluated for uterotrophic and antiuterotrophic activity in the CD-1 mouse. None of the tested compounds shows estrogenic activity in this sensitive in vivo system. At low doses (1 and 3 micrograms), a 14-57% inhibition of E2-induced uterine growth was observed while no additional inhibition was observed at the 10, 20 and 30 micrograms doses. In human breast carcinoma cells in culture, all compounds show estrogenic activity at high concentrations while only compound 39 (N-butyl,N-methyl-8-[3',17' beta-dihydroxy estra-1',3',5'(10')-trien-17' alpha-yl]-7-octynamide) possesses antiproliferative or antiestrogenic effects. No significant correlation could be demonstrated between alkynylamide side chain length and estrogenic or antiestrogenic activity. Among the compounds tested, the derivative of EE2 possessing a five-methylene (CH2) side chain (compound 39) possesses the best antiestrogenic activity (44 +/- 7% in the CD-1 mouse uterus assay at the 3 micrograms dose and 57 +/- 4% at 0.1 nM in human ZR-75-1 cancer cells in culture.
J Steroid Biochem Mol Biol 1991 Jun
PMID:Synthesis and biological activity of 17 alpha-alkynylamide derivatives of estradiol. 206 92

Estradiol-2/4-hydroxylase (E-2/4-H) activity was determined in the mouse uterus during early pregnancy as well as in ovarian steroid hormone-treated ovariectomized uterus. Under the assay conditions used, E-4-H was the predominant catechol estrogen-forming monooxygenase enzyme. The inhibition of E-4-H activity by SKF-525A, metyrapone and alpha-naphthoflavone suggested involvement of cytochrome P450-dependent monooxygenases. A haloestrogen, 2-fluoroestradiol (2-FL-E2), also inhibited this activity. During the peri-implantation period, no change in uterine E-4-H activity was noted on the morning of days 2 through 5, but the activity significantly (P less than 0.01) increased in the afternoon of day 4 of pregnancy. A single injection of estradiol-17 beta (E2, 100 ng/mouse) to ovariectomized mice significantly (P less than 0.01) elevated the level of E-4-H activity at 24 h as did injections of progesterone (P4, 2 mg/mouse) for 2 days. When 2 days of P4 (2 mg/mouse) treatment was combined with a single injection of E2 (20 ng/mouse), E-4-H activity increased 1.3-fold (P less than 0.05) by 24 h above that of P4 treatment alone. Dexamethasone (200 micrograms/mouse) and cholesterol (2 mg/mouse) treatment for 2 days had no effect on E-4-H activity. Thus, the stimulatory effect of P4 and E2 on E-4-H activity appeared to be specific. The increased activity of uterine E-4-H prior to implantation on day 4 evening and the modulation of its activity by P4 and/or E2 suggest an involvement of 4-hydroxyestradiol in embryo implantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1990 Feb 12
PMID:Catechol estrogen formation in the mouse uterus and its role in implantation. 215 14

The role of growth factor signal transducers in the induction of the progesterone receptor by epidermal growth factor (EGF) and the potential sites of EGF antagonism by an antiestrogen were studied in fetal uterine cells in culture. The effects of EGF and estradiol were not additive, suggesting that EGF and estradiol are acting through common mechanisms where antiestrogens could possibly intervene. Fetal uterine cells in culture were found to contain specific, high affinity binding sites for [125I]EGF. Estradiol treatment of the cells led to a higher number of binding sites, but the site of action of 4-hydroxytamoxifen is not the EGF receptor because this antiestrogen had no effect on EGF binding. Activation of protein kinase C by a phorbol ester (12-O-tetradecanoylphorbol 13-acetate) increased progesterone receptor levels to a similar extent as EGF or estradiol. Increasing the intracellular cAMP concentrations by either adding dibutyryl cyclic AMP or activating adenylate cyclase with forskolin also raised progesterone receptor concentrations. Neither the phorbol ester nor dibutyryl cAMP had any effect on cell proliferation. 4-Hydroxytamoxifen completely abolished the effects of the phorbol ester and cAMP. In conclusion, the levels of an estrogen-induced steroid hormone receptor can be regulated by molecules involved in the signal transduction pathway of peptide factors. Moreover, in fetal uterine cells, a potent antiestrogen appears to act as a multiple antagonist but only on an estrogen-inducible response.
Mol Cell Endocrinol 1990 Mar 05
PMID:Stimulation of progesterone receptors by phorbol ester and cyclic AMP in fetal uterine cells in culture. 215 66

Hormone effects on proenkephalin (PE) mRNA allow an opportunity to compare a brain region-specific molecular change with a quantifiable behavior. Slot blots were used to measure PE mRNA levels in the ventromedial hypothalamus (VMN) and preoptic area (POA) as a function of the dose of estrogen administered to ovariectomized rats. Every rat used had been characterized for the ability to display lordosis behavior. Estradiol treatment led to a monotonic dose-dependent increase in PE mRNA level in VMN, while only a small effect was observed in POA at the higher estradiol doses. Lordosis behavior, assessed manually and in mating tests, also increased monotonically with estradiol dose. The data indicate that an apparent 'threshold' level of PE mRNA in VMN coincided wit display of behavior, and suggest further that high levels of PE mRNA, alone, are not sufficient for lordosis. While the exact relationship of the eventual product, Met-enkephalin, to female reproductive behavior remains to be determined, the parallel changes in PE mRNA level and behavior encourage further analysis.
Brain Res Mol Brain Res 1990 Jun
PMID:Estradiol induction of proenkephalin messenger RNA in hypothalamus: dose-response and relation to reproductive behavior in the female rat. 216

Several hydroxylated derivatives of tamoxifen were tested for their effects on the growth of T47D human breast cancer cells in vitro. Compounds containing a fused seven-membered ring were used to prevent isomerization of the triphenyl-ethylenes at the double bond. This stable structure permitted the determination of the activity of the cis and trans forms of tamoxifen and the true activity of two of its metabolites, 4-hydroxytamoxifen and metabolite E. Estradiol stimulates the growth of T47D cells 3-4-fold over control after 6 days of treatment (EC50 = congruent to 3 x 10(-12) to 3 x 10(-11) M, depending upon the particular experiment). The fixed ring form of the trans isomer of tamoxifen is an antiestrogen, whereas the cis isomer is estrogenic. Fixed ring-trans-4-hydroxytamoxifen is a potent antiestrogen, and its cis isomer is a weak antiestrogen (IC50 congruent to 4 x 10(-8) to 2 x 10(-7) M). The fixed ring form of trans-metabolite E (tamoxifen without the dimethylaminoethane side chain) is only a weak partial estrogen agonist, whereas the fixed ring derivative of its cis isomer is a potent estrogen agonist (EC50 congruent to 4 x 10(-12) to 1 x 10(-11) M). These studies have determined the true biological activities of the hydroxylated derivatives of tamoxifen. This information will be valuable for the development of drug receptor models and will be particularly useful when the three-dimensional structure of the receptor complex is determined.
Mol Pharmacol 1990 Nov
PMID:Structure-function relationships of hydroxylated metabolites of tamoxifen that control the proliferation of estrogen-responsive T47D breast cancer cells in vitro. 223 1

The possible role of intrauterine estrogen sulfatase and steroid sulfatase around the time of parturition in the guinea pig was investigated. [3H]Estrone sulfate or [3H]pregnenolone sulfate was incubated with intrauterine tissues. Estrogen sulfatase was found in placenta, endometrium, decidua basalis, amnion and chorion. The presence of steroid sulfatase was established in endometrium and decidua basalis but not in placenta or the fetal membranes. Examination of activities in early (days 32-35), mid (days 44-46) and late (within 5 days of parturition) gestation revealed no significant change in estrogen sulfatase specific activity in decidua basalis. However, in chorion and endometrium this activity was seen to increase approx. 12-fold (P less than 0.001) and 2.8-fold (P less than 0.001), respectively, from early to late gestation. In placenta, estrogen sulfatase activity appeared to increase 2.4-fold (P less than 0.001) and in amnion it decreased 2.8-fold (P less than 0.002). Steroid sulfatase activity in decidua basalis did not change during gestation, while activity in endometrium was found to increase by a factor of 5.3 (P less than 0.001), from early to late gestation. The increases, both in estrogen sulfatase activity in chorion, endometrium and placenta and in steroid sulfatase activity in endometrium, occurred primarily within the final 3 weeks of gestation. In contrast, the decrease in estrogen sulfatase activity in amnion occurred principally between the fifth and sixth weeks of gestation. Analysis of radiolabelled metabolites indicated that estradiol and progesterone could be produced via estrogen sulfatase and steroid sulfatase activities in certain tissues. Subcellular fractionation of tissues revealed that the greatest specific activity and total activity, in all cases, was associated with the 105,000 g pellet. Significant activity was also detected in the 750 and 10,000 g pellets but not in the 105,000 g supernatant. Radioimmunoassay of endogenous estradiol-17 beta (estradiol) in chorion extracts revealed a 6.3-fold increase in the hormone from mid to late gestation. Estradiol levels in endometrium and myometrium did not appear to change during this time. It was concluded that increased estrogen sulfatase activity in guinea pig chorion in late gestation occurs along with elevated levels of the hormone estradiol which may be important for parturition in this species.
J Steroid Biochem Mol Biol 1990 Dec 10
PMID:Estrogen sulfatase and steroid sulfatase activities in intrauterine tissues of the pregnant guinea pig. 227 54

Both estrogens and androgens have been shown to stimulate sex hormone binding globulin (SHBG) secretion in vitro in the hepatocellular carcinoma cell line, Hep G2, in contrast to the expected inhibition by androgens from in vivo studies. However, such in vitro stimulation was only demonstrated at high steroid doses, generally in serum-containing medium, with added Phenol Red. In the present study, Hep G2 cells were grown in serum-free medium, without Phenol Red, under the influence of testosterone (T) (0, 0.5-500 nM) and ethinyl estradiol (EE2) (0, 50 pM-500 nM). Levels of secreted SHBG and albumin were correlated with androgen receptors in cytosolic (ARc) and nuclear (ARn) fractions and with DNA levels. In the presence of increasing T levels, SHBG levels fell to 39% of control values at 5 nM T (P = 0.047), rising to 97% of control at 500 nM. Conversely, incubation with EE2 produced a rise in SHBG secretion of more than 100% at 0.5 nM (P less than 0.02) which was sustained to 50 nM (P less than 0.005). DNA levels did not change with the addition of testosterone or EE2, with the exception of a 15% reduction at 5 nM EE2 (P less than 0.05). Albumin levels in the medium were not significantly altered by either steroid. However, in response to T, androgen receptor (AR) levels were reduced in cytosolic (42% of control) and nuclear (22%) fractions at 5 nM, and these changes in ARc and ARn correlated with SHBG levels over the range of T concentrations (P = 0.04 and P = 0.017, respectively). Nuclear estrogen receptor (ER) increased over 10-fold at 5 and 50 pM EE2 (P less than 0.001) and maintained 50 nM (P less than 0.001). Cytosolic ER was reduced at 0.5 and 5 nM but recovered at 50 nM, correlating with SHBG levels (P less than 0.001). These findings are consistent with the hypothesis that estrogens and androgens regulate SHBG synthesis in man by direct, specific, probably receptor-mediated effects on hepatocytes. Hep G2 cells grown in serum-free medium are a suitable experimental system for further study of this phenomenon.
J Steroid Biochem Mol Biol 1990 Dec 10
PMID:Estrogen and androgen regulation of sex hormone binding globulin secretion by a human liver cell line. 227 57


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