Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4-Hydroxy-4-androstene-3,17-dione (4-OHA) and 4-acetoxy-4-androstene-3,17-dione (4-AcA), in addition to being competitive inhibitors of aromatase, cause time-dependent, irreversible, loss of enzyme activity in both human placental and rat ovarian microsomes. In vivo, treatment of rats with 4-OHA also causes loss of ovarian aromatase activity. To test whether this loss of activity could have in vivo significance, rats with hormone-dependent, mammary tumors were treated with 4-OHA on alternate weeks. Tumor regression continued to occur during the weeks without treatment. These findings suggest that inactivation of aromatase is important in the mechanism of action of the compounds in vivo.
Steroids 1981 Dec
PMID:Inactivation of aromatase in vitro by 4-hydroxy-4-androstene-3,17-dione and 4-acetoxy-4-androstene-3,17-dione and sustained effects in vivo. 733 66

Adrenal gland homogenates from four different strains of mice were incubated with (4-14C)-pregnenolone and a NADPH generating system. Although quantitative differences between high and low mammary tumor strains occured, all mice synthesized estrone. The highest aromatase activity was found 2 months after castration of the (C3H x RIII) F1 mice when castration was performed at 4 days of age; this activity was lower in the C3H mice and almost negligible in the RIII and C57BL mice.
Steroids 1980 Apr
PMID:In vitro pregnenolone metabolism by mouse adrenal gland: I-estrogen synthesis. 737 27

The inhibition of aromatase enzyme in human breast tumors by delta 1-testololactone, testololactone, 6 alpha-bromoandrostenedione, and 6 beta-bromoandrostenedione was investigated. Estrone and estradiol synthesis from androstenedione was reduced in 3 tumor incubations by the presence of 0.13 mM delta 1-testololactone and testololactone. 6 alpha- and 6 beta-bromoandrostenedione (2.0 microM) were also shown to block estrogen synthesis in 2 tumors. Furthermore, Lineweaver-Burk plots revealed that all 4 compounds are competitive inhibitors of androstenedione aromatization. An apparent Km of the aromatase enzyme for androstenedione of 0.08 microM and a Vmax of 23 pmol of estrone synthesized/g tumor/hr were determined for one human breast tumor specimen. These results demonstrate that these aromatase inhibitors may be useful for the treatment of breast cancer.
Steroids 1980 May
PMID:Inhibition of estrogen synthesis in human breast tumors by testololactone and bromoandrostenedione. 739 58

Using an accurate and sensitive assay for the human placental aromatase we have found apparent Km values for androstenedione (4-androstene-3,17-dione) and testosterone to be 14 +/- 4.0 nM and 41 +/- 12 nM respectively. These values were significantly different (p < 0.001). Analyses at substrate concentrations 5-10 fold above and below the Km values did not indicate any anomalous kinetic behavior. Mixed substrate experiments were consistent with a single enzyme metabolizing both steroids: each competitively inhibited the aromatization of the other, and the "Ki" values were the same as their apparent Km values. Sodium chloride (1.2M) significantly increased the rate of testosterone aromatization by decreasing its Km value and had no significant effect on the aromatization of androstenedione. However, in the presence of this salt testosterone still inhibited the aromatization of androstenedione competitively with a "Ki" equal to its apparent Km. Our data is therefore consistent with the proposal that human placental microsomes contain a single "high affinity" site for the aromatization of androstenedione and testosterone.
Steroids 1980 Nov
PMID:Substrate specificity of the placental microsomal aromatase. 745 98

The synthesis and biological evaluation of 4-thiosubstituted derivatives of 1,4-androstadienedione, 4,6-androstadienedione, and 1,4,6-androstatrienedione as inhibitors of aromatase are described. Inhibitory activity of synthesized compounds was assessed using a human placental microsomal preparation as the enzyme source and [1 beta-3H]androstenedione as substrate. Under initial velocity assay conditions of low product formation, the inhibitors demonstrated potent inhibition of aromatase, with apparent Kis ranging from 9.8 to 137 nM and with Km for androstenedione being 38 nM. However, unlike other 1,4-androstadienediones and 1,4,6-androstatrienediones in which time-dependent inactivation was observed, the 4-thiosubstituted analogs were found to be competitive inhibitors and did not produce any time-dependent inactivation of aromatase.
Steroids 1995 May
PMID:Aromatase inhibitors: effect of ring A and ring B unsaturation on aromatase inhibition by 4-thiosubstituted derivatives of 4-androstene-3,17-dione. 757 Jul 17

A study of a large cell calcifying Sertoli cell tumor of the testis associated with bilateral gynecomastia in an 8-year-old boy is presented. Macroscopically, the two testes showed multiple, large, and hard calcified nodules. Histology revealed clusters or cords of tumor cells with foci of calcifications as well as evidences, in the adjacent testicular parenchyma, of initiation of gonadal development, such as early signs of spermatogenesis and sparse Leydig cell differentiation. In vivo, serum hormone studies showed gonadotropin-independent gonadal activity. After orchidectomy two macroscopically distinct fractions of the removed testes, tumoral and extratumoral, were processed separately for cell isolation and culture. The secretion of testosterone, androstenedione, and 17-hydroxyprogesterone to the medium on day 6 of culture showed that steroidogenesis in cells of the extratumoral fraction was more active than in the tumoral fraction. On the other hand, tumoral fraction cells showed much higher aromatase activity than extratumoral cells. Furthermore, conditioned medium of tumoral fraction cells was able to stimulate testosterone secretion when it was added to subcultures of testicular cells isolated from a control subject. It is postulated that tumoral cells might have stimulated neighboring interstitial cells to differentiate into Leydig cells and to secrete androgens, which in turn might have been aromatized to estrogens by tumoral cells.
Steroids 1995 Feb
PMID:Testicular steroid biosynthesis in a boy with a large cell calcifying Sertoli cell tumor producing prepubertal gynecomastia. 761 89

Mifepristone (RU 486), used clinically for the termination of early pregnancy, and its acetyl and 13-retro (13 alpha) analogs show potent antiproliferative effects against estrogen-dependent human breast tumors and endometriosis. However, there has been no report on direct inhibition of aromatase by antiprogesterones. Aromatase inhibitors have been shown to be effective against estrogen-dependent breast cancer. We evaluated the inhibition of aromatase by various antiprogestins (ZK 112.993, ZK 98.734, ZK 114.043, ZK 98.299, and ZK 114.863). Human placental microsomes were incubated with [1 beta-3H,4-14C] androstenedione (3-114 nM) in the presence of NADPH, with or without putative inhibitors (10-200 microM). Aromatase activity was assessed by tritium release to water from the 1 beta-position of the substrate. ZK 112.993 and ZK 98.734 did not show any inhibitory effect. The statistical analysis of the data using standard errors was obtained from replicate experiments. ZK 114.043 showed slight inhibition with a Ki of 54.8 +/- 6.4 microM (m +/- SE, n = 6) against androstenedione aromatization. The two 13-retro-steroids, ZK 98.299 and ZK 114.863, showed aromatase inhibition with Ki values of 19.0 +/- 1.5 microM (n = 7) and 12.7 +/- 0.94 microM (n = 7), respectively, which is weak with respect to some known potent inhibitors, but significant when compared with the other antiprogestins which were tested. The results suggest that the unnatural 13-retro-antiprogestin conformation may have a better fit to the aromatase active site than the natural 13 beta-antiprogestin conformation. (Steroids 60:234-238, 1995).
Steroids 1995 Feb
PMID:Inhibition of aromatase activity in human placental microsomes by 13-retro-antiprogestins. 761 91

2,2-Dimethylandrost-4-ene-3,6,17-trione (5) and its 4-methoxy- (7) and 4-hydroxy- (8) derivatives were synthesized. 7 alpha-Acetoxy-4-ene-3,6-dione steroid 2 was also prepared by the improved method involving the lead tetraacetate oxidation of androst-4-ene-3,6,17-trione (1). These steroids along with the 2-acetoxy-(11 and 12), 2-substituted 1-ene- (9 and 10), and 4-substituted (13-15) derivatives of compound 1 were evaluated as inhibitors of human placental aromatase. All the steroids, except the 2-acetoxy-1-ene 10 and the 2 beta-acetate 11 of which Ki values were not determined because of their poor inhibitory activities, blocked aromatase in a competitive manner. Compounds 5 and 8 as well as the 4-hydroxy steroid 15 were potent inhibitors (Ki: 25-42 nM) whereas the inhibitory activities of steroids 2, 7, 9, 13, and 14 were good to fair, respectively (Ki: 160-810 nM). Inhibitors 2 and 15 inactivated the enzyme in a time-dependent manner in the presence of NADPH but the 2,3-dimethyl derivatives 5 and 8 did not. Androstenedione blocked the inactivation but L-cysteine did not. The results suggest that the 2 beta-methyl group would prevent the aromatase-catalyzed oxygenation at C-19 of the dimethyl steroids 5 and 8 most likely through the steric reasons.
Steroids 1994 Oct
PMID:A- or B-ring-substituted derivatives of androst-4-ene-3,6,17-trione as aromatase inhibitors. Structure-activity relationships. 787 85

A series of androst-5-en-7-ones and androsta-3,5-dien-7-ones and their 7-deoxy derivatives, respectively, were synthesized and tested for their abilities to inhibit aromatase in human placental microsomes. All the steroids inhibited the enzyme in a competitive manner with Ki's ranging from 0.058 to 45 microM. The inhibitory activities of 17-oxo compounds were much more potent than those of the corresponding 17 beta-alcohols in each series. Steroids having an oxygen function (hydroxy or carbonyl) at C-19 were less potent inhibitors than the corresponding parent compounds having a 19-methyl group. 3,5-Dien-7-one 24 and its 19-hydroxy and 19-oxo derivatives (12 and 13) as well as 19-oxo-5-en-7-one 3 caused a time-dependent inactivation of aromatase only in the presence of NADPH in which the kinact values of 19-als 3 and 13 (0.143 and 0.189 min-1, respectively) were larger than those of the corresponding 19-methyl (23 and 24) and 19-hydroxy (1 and 12) steroids, respectively. 19-Nor-5-en-7-one 4 but not its 3,5-diene derivative 14 also inactivated the enzyme in a time-dependent manner. In contrast, 7-deoxy steroids 21 and 27, having a 19-methyl group, did not cause it. The inactivations were prevented by the substrate androstenedione, and no significant effects of L-cysteine on the inactivations were observed in each case. The results suggest that oxygenation at C-19 would be at least in part involved in the inactivations caused by the inhibitors 23 and 24. The conjugated enone structures should play a critical role in the inactivation sequences.
 ...
PMID:Synthesis of androst-5-en-7-ones and androsta-3,5-dien-7-ones and their related 7-deoxy analogs as conformational and catalytic probes for the active site of aromatase. 803 27

Several 7 alpha-thiosubstituted derivatives of androstenedione have demonstrated effective inhibition of aromatase, the cytochrome P450 enzyme complex responsible for the biosynthesis of estrogens. Introduction of an additional double bond in the A ring resulted in 7 alpha-(4'-amino)phenylthioandrosta-1,4-diene-3,17-dione (7 alpha-APTADD), a potent inhibitor that inactivated aromatase by an enzyme-catalyzed process. Additional 7 alpha-thiosubstituted androsta-1,4-diene-3,17-dione derivatives were designed to further examine enzyme-catalyzed inactivation. Two halogenated and one unsubstituted 7 alpha-phenylthioandrosta-1,4-diene-3,17-diones were synthesized via an acid-catalyzed conjugate Michael addition of substituted thiophenols with androsta-1,4,6-triene-3,17-dione. Two 7 alpha-naphthylthioandrosta-1,4-diene-3,17-diones were synthesized via either acid-catalyzed or based-catalyzed conjugate Michael addition of substituted thionaphthols with androsta-1,4,6-triene-3,17-dione. These agents were evaluated for aromatase inhibitory activity in the human placental microsomal preparation. Under initial velocity assay conditions of low product formation, the inhibitors demonstrated potent inhibition of aromatase, with apparent Ki's ranging from 12 to 27 nM. Furthermore, these compounds produced time-dependent, first-order inactivation of aromatase in the presence of NADPH, whereas no aromatase inactivation was observed in the absence of NADPH. This enzyme-activated irreversible inhibition, also referred to as mechanism-based inhibition, can be prevented by the substrate androstenedione. Thus, the apparent Ki values for these inhibitors are consistent with earlier studies on 7 alpha-substituted competitive inhibitors that indicate bulky substituents can be accommodated at the 7 alpha-position.(ABSTRACT TRUNCATED AT 250 WORDS)
Steroids 1993 Sep
PMID:Synthesis and biochemical studies of 7 alpha-substituted androsta-1,4-diene-3,17-diones as enzyme-activated irreversible inhibitors of aromatase. 823 27


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