Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biological importance of aromatase rests in the concept that this is the rate-limiting enzyme involved in estrogen biosynthesis. Approx. one-third of human breast carcinomas depend upon estrogen for growth. Blockade of estrogen biosynthesis, then, provides an effective means of causing tumor regression in selected patients. The side effects and lack of specificity of the aromatase inhibitor, aminoglutethimide, provided the impetus toward development of nonsteroidal inhibitors of aromatase. Several compounds are currently being evaluated. Pyridoglutethimide is a derivative of aminoglutethimide which does not inhibit cholesterol side-chain cleavage and possesses no CNS sedative properties; the Ki for aromatase is 1100 nM, somewhat higher than for aminoglutethimide, 600 nM. CGS 16949A is a highly potent inhibitor of aromatase which is an imidazole derivative. This compound inhibits aromatase with a Ki of 0.19 nM whereas inhibition of C11-hydroxylase activity occurs at 10(-6) M. In clinical trials, this compound lowers plasma estrogen levels, blocks peripheral aromatization as documented by isotopic kinetic studies, and causes tumor regression. Phase III trials with this drug are now ongoing. Another agent, R76713, represents another highly potent and specific aromatase inhibitor with little toxicity in animal studies. The Ki for placental aromatase is 0.8 nM and this compound is approx. 500-fold more potent than aminoglutethimide. Phase I clinical studies in patients reveal a marked reduction in estrogen production. These compounds represent the most promising of a wide variety of agents currently being tested for their aromatase inhibitory properties.
J Steroid Biochem Mol Biol 1991
PMID:Clinical use of aromatase inhibitors in human breast carcinoma. 183 44

19-Nordeoxycorticosterone (19-norDOC) is a powerful mineralocorticoid, which has been postulated to be involved in the pathogenesis of some forms of hypertension. The urinary excretion of 19-norDOC by female rats is up to 20 times that of males. To demonstrate the influence of the gonads on the excretion of 19-norDOC, we measured the excretion of 19-norDOC in intact and gonadectomized male and female rats with and without replacement with testosterone (40 mg testosterone enanthate s.c.) or estrogen (4 mg estradiol valerate s.c.) and in intact animals receiving the aromatase inhibitor, 10-propargyl androstenedione (10-pA) (10 mg s.c.). Orchiectomy produced a significant increase in the urinary excretion of 19-norDOC in males. Testosterone treatment decreased 19-norDOC excretion by castrated males to below intact values, while estrogen administration increased its excretion. Oophorectomy had no consistent effect on 19-norDOC excretion. In oophorectomized females, testosterone administration significantly suppressed 19-norDOC excretion and estrogen replacement increased excretion slightly. 10-pA had little effect on the excretion of 19-norDOC in intact rats of either sex. In conclusion, it appears that 19-norDOC production is inhibited by testosterone, but is affected only slightly by estrogens.
J Steroid Biochem Mol Biol 1991 Aug
PMID:The effect of gonadectomy and aromatase inhibition on the excretion of 19-nordeoxycorticosterone in rats. 188 77

Estrogen synthetase (aromatase) catalyzes the conversion of androgen into estrogen via two hydroxylations at C19 and a subsequent C19-10 lyase reaction. We report here the results of a reconstitution study using a highly purified aromatase cytochrome P450 monooxygenase enzyme system, with both protein components (cytochrome P450 and NADPH-cytochrome P450 reductase) obtained from human term placental microsomes. By varying one of the components (amounts of cytochrome P450, NADPH-cytochrome P450 reductase, or androgen substrate) as the other two were held constant in four different environments (phospholipid, non-ionic detergent, mixture of phospholipid and non-ionic detergent and buffer alone), we obtained evidence supporting the following conclusions. The reconstituted enzyme is more active and the protein components exhibit much lower apparent Km values in the detergent and/or lipid environment compared with buffer alone. Although the apparent Km and Vmax values for each aromatase protein component differ significantly in most cases with the particular limiting component and environment, the catalytic efficiency (Kcat/Km) was independent of the limiting protein component and varied with the environment only (highest in the lipid-detergent mixture and lowest in lipid alone). When the concentration of androgen substrate (androstenedione or testosterone) was varied at constant amounts of the aromatase protein components (NADPH-cytochrome P450 reductase saturating), the Km was lower and the Vmax was higher for adrostenedione. The specificity constant (Vmax/Km) was a function of the reconstitution environment (highest in lipid alone and lowest in detergent alone) and was, on average, about 4-fold higher for androstenedione in a particular environment. The extent of production of 19-oxygenated androgen intermediates (19-hydroxy and 19-oxo androstenedione) was examined at three different levels of aromatase cytochrome P450 (subsaturating, saturating, super-saturating) relative to the NADPH-cytochrome P450 reductase component in the three different hydrophobic environments using androstenedione as substrate. Both 19-oxygenated androgens, each made in comparable amounts relative to control, were isolatable in greatest amounts under cytochrome P450 super-saturating conditions in the detergent-lipid mixed environment, and in least amounts under cytochrome P450 subsaturating conditions in the lipid-only environment. Based on these data, we propose that 19-oxygenated androgen intermediates are biosynthesized sequentially in a step-wise fashion as the cytochrome P450 and NADPH-cytochrome P450 reductase form transient complexes, and that the amount of isolatable 19-oxygenated androgen is proportional to the amount of excess cytochrome P450 component.
J Steroid Biochem Mol Biol 1991 Sep
PMID:Human placental estrogen synthetase (aromatase). Effect of environment on the kinetics of protein-protein and substrate-protein interactions and the production of 19-oxygenated androgen intermediates in the purified reconstituted cytochrome P450 enzyme system. 191 29

The role of carbohydrate-poor (Con A I) and carbohydrate-rich (Con A II) pituitary protein fractions, isolated from sockeye salmon (Oncorhynchus nerka), were investigated pertaining to in vitro estradiol-17 beta (E2) production by rainbow trout (Oncorhynchus mykiss) ovarian follicles. During the early vitellogenic phase of the reproductive cycle, using defolliculated ovarian follicle preparations (outer epithelium-thecal layer absent), it was demonstrated that the Con A I fraction was capable of increasing E2 production, in the presence of exogenous testosterone (T) as the substrate. Under similar conditions the Con A II fraction (containing the maturational gonadotropin) was inactive. However the Con A II fraction or T, separately, increased E2 production by intact ovarian follicles, whereas the Con A I fraction did not. A mechanism proposed to explain the regulation of ovarian E2 synthesis involves the Con A I fraction enhancing aromatase activity in granulosa cells permitting an increased conversion of T to E2.
J Steroid Biochem Mol Biol 1991 Oct
PMID:Stimulation of in vitro ovarian estradiol-17 beta synthesis in the rainbow trout by the carbohydrate-poor protein fraction from sockeye salmon pituitary glands. 191 40

Estrogen synthetase (aromatase) is a cytochrome P-450 enzyme system which converts androgens to estrogens. Although this enzyme has been purified and the cDNA-derived amino acid sequence elucidated, very little is known regarding post-translational modifications of this physiologically crucial enzyme. We show here that the cytochrome P-450 component, P-450ES, purified from human term placental microsomes, is a glycoprotein based on the following evidence: its molecular weight is decreased following treatment with endoglycosidase F, concanavalin A-biotin specifically binds to this protein immobilized on nitrocellulose, and its oligosaccharide composition is consistent with a single N-linked fucosylated complex type carbohydrate chain. In a reconstitution system, the aromatase activity using the endoglycosidase F-treated P-450ES was reduced by about 35-40% relative to the native form, regardless of whether androstenedione or testosterone was used as substrate.
Mol Cell Endocrinol 1991 Jun
PMID:Estrogen synthetase (aromatase). The cytochrome P-450 component of the human placental enzyme is a glycoprotein. 193 23

Direct roles of follicle-stimulating hormone (FSH)-suppressing protein (FSP) and activin in regulation of ovarian granulosa cell differentiation have been reported recently. The present study further investigated the effects of these peptides on steroidogenesis and inhibin production as well as cAMP generation in cultured granulosa cells from immature, diethylstilbestrol (DES)-treated rats. In the presence of FSH (20 ng/ml) and activin (30 ng/ml), which enhanced FSH-induced aromatase activity, progesterone production and inhibin production, FSP (1-100 ng/ml) reversed the stimulating activities of activin in a dose-dependent manner. In addition, activin reversed the inhibitory effects of FSP on FSH-induced aromatase activity and inhibin production. In the presence of FSH, activin enhanced FSH-stimulated extracellular cAMP accumulation, and FSP caused a reduction in extracellular cAMP. Activin but not FSP also stimulated basal cAMP level. In the presence of forskolin, a potent stimulant of adenyl cyclase activity which stimulated extracellular cAMP, aromatase activity, progesterone production and inhibin production, activin augmented the effect of forskolin on all four parameters, whereas FSP significantly enhanced progesterone production without changing the other three parameters. Our findings suggest that activin action on rat granulosa cells may be mediated via regulation of cAMP generation. The action of FSP and FSH and/or activin-dependent, consistent with either an action as an activin binding protein or by a direct action of FSP on the granulosa cells.
Mol Cell Endocrinol 1991 Aug
PMID:Interactions between activin and follicle-stimulating hormone-suppressing protein and their mechanisms of action on cultured rat granulosa cells. 193 50

Aromatase activity may be detected both in breast adipose tissue and breast cancer in levels similar to or greater than those in other peripheral tissues. Factors influencing such local biosynthesis have been sought. Of 247 primary breast cancers investigated, 178 showed evidence of oestrogen biosynthesis. No significant relationships were found between either the presence or levels of activity and tumour histopathology, patient characteristics (such as age and menopausal status), disease stage and prognosis (determined by disease-free interval and survival after primary treatment). Aromatase was more likely to be found in cellular cancers and those which were oestrogen receptor-positive, but these were not absolute associations, activity being detected in tumours with all degrees of cellularity and both receptor-positive and receptor-negative cancers. However, in a small group of patients with metastatic oestrogen receptor-positive tumours, response to the aromatase inhibitor, aminoglutethimide, seemed confined to tumours with aromatase activity. Oestrogen biosynthesis was detected in all specimens of breast adipose tissue examined. Activities were higher in fat from breast cancer patients compared with that from women with benign breast disease. In breasts with cancer, levels were higher in quadrants bearing tumour compared with those without evidence of malignancy. It is suggested that either enhanced aromatase in breast fat promotes the appearance of overt cancer or tumour factors induce aromatase in surrounding fat. Finally, although no significant correlations were detected in postmenopausal women between local aromatase activity and endogenous oestrogens in breast cancer, perfusion studies show that in situ oestrogen biosynthesis is primarily responsible for oestrogen levels in the majority of breast tissues. These data suggest that local aromatase activity may influence events within the breast and may be associated with the natural history and progression of certain malignancies.
J Steroid Biochem Mol Biol 1991 Nov
PMID:Aromatase activity in breast tissue. 195 67

To test the hypothesis of an increased activity of the enzyme aromatase in adipose tissue from affected when compared with non-affected quadrants of patients with breast cancer, the aromatase activity has been measured in tumour and fatty tissues dissected at specific sites from the breasts of 16 patients. Activity was measured after extensive purification of the product formed. Results, expressed in fmol/g of tissue, did not show a higher activity in the affected vs the non-affected quadrants. In the tumours, higher activities were found when expressed per g of tissue. Per mg of DNA, an indicator of the number of cells, tumour enzymatic activity was lower than in fatty tissues. The relations between the products of aromatase, oestrone and oestradiol in the various tissues point to the importance of additional enzymatic processes, especially of the reductive 17 beta-oestradiol dehydrogenase, in the accumulation of high quantities of oestradiol in the malignant tissue.
J Steroid Biochem Mol Biol 1991 Nov
PMID:Endogenous steroid hormones and local aromatase activity in the breast. 195 69

The most important mitogen for human breast cancer is oestrogen. Since oestrogens are synthesized via a protracted series of enzymic conversions from cholesterol, there are many potential targets for inhibition which could theoretically lead to suppression of oestrogen synthesis. However, inhibition of many of these targets is complicated by a resultant interference in the synthesis of other steroids, particularly glucocorticoids. This results in inhibitors of aromatase being the most rational choice for oestrogen suppression in breast cancer patients. Several aromatase inhibitors are in clinical usage. It is important that the clinical effectiveness of these is compared with that of the antioestrogen, tamoxifen.
J Steroid Biochem Mol Biol 1991 Nov
PMID:Inhibitors of steroidogenic enzymes for the treatment of breast cancer. 195 70

Estrogen synthesis by aromatase occurs in a number of tissues throughout the body. Strategies which reduce production of estrogen offer useful means of treating hormone-dependent breast cancer. Initially, several steroidal compounds were determined to be selective inhibitors of aromatase. The most potent of these, 4-hydroxyandrostenedione (4-OHA) inhibits aromatase competitively but also causes inactivation of the enzyme. A number of other steroidal inhibitors appear to act by this mechanism also. In contrast, the newer imidazole compounds are reversible, competitive inhibitors. In vivo studies demonstrated that 4-OHA inhibited aromatase activity in ovarian and peripheral tissues and reduced plasma estrogen levels in rat and non-human primate species. In rats with mammary tumors, reduction in ovarian estrogen production was correlated with tumor regression. 4-OHA was also found to inhibit gonadotropin levels in animals in a dose-dependent manner. The mechanism of this effect appears to be associated with the weak androgenic activity of the compound. Together with aromatase inhibition, this action may contribute to reducing the growth stimulating effects of estrogen. A series of studies have now been completed in postmenopausal breast cancer patients treated with 4-OHA either 500 mg/2 weeks or weekly, or 250 mg/2 weeks. These doses did not affect gonadotropin levels. Plasma estrogen concentrations were significantly reduced. Complete or partial tumor regression occurred in 26% of the patients and the disease was stabilized in 25% of the patients. The results suggest that 4-OHA is of benefit to postmenopausal patients who have relapsed from prior hormonal therapies. Several of the steroidal inhibitors are now entering clinical trials as well as non-steroidal compounds which are more potent and selective than aminoglutethimide. Aromatase inhibitors should provide several useful additions to the treatment of breast cancer.
J Steroid Biochem Mol Biol 1991
PMID:Aromatase and its inhibitors--an overview. 195 29


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