Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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When measured in vitro using human placental microsomal preparations, the aromatization of 16alpha-hydroxytestosterone to estriol and androstenedione to estrone and estradiol proceeds at almost identical initial rates. Important differences between 16alpha-hydroxytestosterone and adrostenedione aromatization are evident, however. While substantial findings have implicated cytochrome P-450 in placental aromatization, the aromatizaiton of androstenedione is insensitive to CO although it is competitively inhibited by metyrapone. 16alpha-Hydroxytestosterone aromatization, in contrast, is inhibited 50-60% by CO and is strongly inhibited by metyrapone. 16alpha-hydroxytestosterone aromatization is strongly inhibited in a competitive manner by androstenedione, while 16alpha-hydroxytestosterone has essentially no effect on androstenedione aromatization, althogh at very high 16alpha-hydroxytestosterone concentrations (65 muM) and subsaturating androstenedione concentrations, 16alpha-hydroxytestosterone appears to noncomptitively inhibit androstenedione aromatization. The apparent Km for the aromatization of androstenedione is 95 nM and for 16alpha-hydroxytestosterone, 7 muM. Both androstenedione and 16alpha-hydroxytestosterone cause type I spectral perturbations associated with binding to cytochrome P-450 when added to placental microsomes; however, the deltaA390-420 is twice as great in response to saturating amounts of androstenedione than in response to 16alpha-hydroxytestosterone. If androstenedione is added to 16alpha-hydroxytestosterone, the same spectral change as that caused by androstenedione alone is expressed. The apparent spectral dissociation constant for androstenedione is 93 nM while for 16alpha-hydroxytestosterone it is 11muM; both essentially the same as the comparable apparent Kms for aromatization. The evidence suggests the presence of two aromatase P-450's in human placenta.
Mol Cell Endocrinol 1976 Dec
PMID:Cytochrome P-450 and the aromatization of 16alpha-hydroxytestosterone and androstenedione by human placental microsomes. 100 10

We have previously shown that human breast cancer is autonomous in the regulation of its intra-tissue oestradiol concentration. Breast fatty tissue does not have this capacity, but rather reflects changes in the peripheral oestradiol concentration. To further evaluate the relative contribution of breast cancer and fatty tissue to the maintenance of tumour oestradiol we investigated whether a tumour-directed gradient in aromatase activity and oestrogen levels existed in mastectomy specimens. No such gradient was found, however, for aromatase, oestrone, oestradiol and their sulphates. Aromatase activity (expressed per gram of tissue) and the concentrations of oestradiol, oestradiol sulphate and oestrone sulphate were higher in tumour than in breast fatty tissue. Fatty tissue had a higher oestrone concentration. It is tentatively concluded that breast tumour aromatase activity is more important for the maintenance of tumour oestradiol levels than aromatase in breast fatty tissue.
J Steroid Biochem Mol Biol 1992 Mar
PMID:On the significance of in situ production of oestrogens in human breast cancer tissue. 131 86

The aromatase cytochrome P-450 (P-450AROM) cDNA, which was identified by homologies in the DNA and in the deduced amino acid sequences with human P-450AROM cDNA, was isolated from a brain cDNA library of Japanese quail, demonstrating the presence of RNA transcripts of P-450AROM in the quail brain. To determine trace amounts of P-450AROM mRNA in the brain and to examine the effects of testosterone on its expression, a quantitative PCR method of RNA transcripts was developed. Brain total RNA was subjected to reverse transcription reaction and then quantitated by PCR from cDNA with a fluorescent dye-labeled primer. The quantity of P-450AROM mRNA was calculated by using an internal standard of modified P-450AROM (m-P-450AROM) RNA. The brain P-450AROM was primarily transcribed in the hypothalamus area (1.15 +/- 0.14 amol/micrograms of RNA) and traces of transcripts only were detected in the cerebellum (0.038 +/- 0.005 amol/micrograms of RNA). The P-450AROM mRNA in the hypothalamus of castrated quail was low (0.270 +/- 0.078 amol/micrograms of RNA) and increased 4- to 5-fold following treatment with testosterone. These results demonstrate, for the first time, that the increase in P-450AROM activity that is observed in the brain following treatment with testosterone results from a pretranslational regulation of the P-450AROM by androgens.
Brain Res Mol Brain Res 1992 Sep
PMID:Regulation of aromatase cytochrome P-450 (estrogen synthetase) transcripts in the quail brain by testosterone. 133 67

Aromatase, a cytochrome P-450, catalyzes the formation of aromatic C18 estrogenic steroids from C19 androgens. DNA sequence analysis of the human aromatase gene has revealed that a putative promoter sequence exists immediately up-stream of the second exon. Chloramphenicol acetyltransferase functional analyses of cells transfected with chloramphenicol acetyltransferase expression plasmids containing various DNA fragments derived from the 3'-end of the first intron of the aromatase gene were performed to show that a promoter indeed exists in this region. However, in all of the cell lines used in this study, MCF-7, JAR, OVCAR-3, and skin fibroblast, the function of this promoter was inhibited by a negative regulatory element situated up-stream from the promoter. The results further suggest that this inhibitory element behaves as a silencer element, in that it could inhibit a simian virus-40 promoter from a distance of several kilobases. This negative element worked in both orientations and inhibited the functions of several promoters, including the newly identified promoter situated in the 3'-end of the first intron of the human aromatase gene. Primer extension analysis has been performed to determine the potential transcription start site. The mechanism of the regulation of aromatase expression is known to be very complex. The presence of a promoter and a silencer at the 3'-end of the first intron may represent one additional way that aromatase expression is controlled in estrogen-producing cells.
Mol Endocrinol 1992 Sep
PMID:Identification of a promoter and a silencer at the 3'-end of the first intron of the human aromatase gene. 133 79

We have previously reported the isolation and characterization of the human gene encoding aromatase cytochrome P-450 (P-450AROM). The gene had been demonstrated to span at least 52 kb and contain ten exons, the first of which, exon I.1, is untranslated. Here we report the isolation and characterization of a P-450AROM cDNA from a human placental primer-extended cDNA library which contains a unique 5' sequence. This cDNA has been isolated and sequences used to screen a human placental genomic library for the presence of a unique first exon. The exon (exon I.2) lies 9 kb 5' of the second, ATG-containing exon (exon II) and is spliced onto exon II at the same site as that reported for exon I.1. DNA sequence analysis indicates that exon I.2 has a putative TATA (TAAA) sequence 33 base pairs (bp) upstream from a putative transcription start site and putative CAAT (CATT) binding sequence beginning at 54 bp upstream from this start site. Polymerase chain reaction (PCR) amplification experiments indicate that mRNA containing exon I.2-specific sequences can be demonstrated in tissues of fetal, but not adult, origin. These data have been confirmed by Northern analysis in the placenta. Characterization of this genomic clone containing exons I.2 and II now establishes the P-450AROM gene to be at least 72 kb in length and raises new questions regarding tissue specific and developmental control of aromatase expression in the human.
Mol Cell Endocrinol 1992 Jan
PMID:Alternative promotion of aromatase P-450 expression in the human placenta. 137 68

Aromatase inhibition in postmenopausal women causes a marked fall in the plasma levels of oestrogens and is an effective treatment for breast cancer, however, trials with aminoglutethimide found that this aromatase inhibitor was ineffective in suppressing plasma oestrogen levels in premenopausal breast cancer patients. We found that the more potent inhibitor, 4-hydroxyandrostenedione (4-OHA), which can suppress oestrogen synthesis in rodents and non-human primates with intact ovarian function, was also unsuccessful as an oestrogen suppressant in premenopausal women at its maximum tolerated dose (500 mg/week i.m.). GnRH agonists are effective suppressants of ovarian oestrogen synthesis but oestrogen production from peripheral sites is unaffected. Our studies of a combination of the GnRH agonist goserelin and 4-OHA demonstrated that the combination caused greater oestrogen suppression than goserelin alone and led to objective clinical response in 4/6 breast cancer patients after their relapse from treatment with goserelin as a single agent. The combination of a GnRH agonist and an aromatase inhibitor should be subjected to clinical trials.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Aromatization inhibition alone or in combination with GnRH agonists for the treatment of premenopausal breast cancer patients. 138 47

Eighty previously treated postmenopausal women with metastatic breast cancer were randomized to receive fadrozole (CGS 16 949A), a new aromatase inhibitor, 1 or 4 mg orally per day. Seventy eight patients were evaluable for toxicity and response. Only mild to moderate toxicity, namely hot flushes (28%), nausea and vomiting (13%), fatigue (8%) and loss of appetite (5%) occurred. Complete response was documented in 10% and partial response in 13% of patients with 45% having a no change status for at least 2 months. The median time to treatment failure is 4.1 months. The median survival is 23.7 months. The median survival is 23.7 months. The response and survival in patients with estrogen receptor positive and estrogen receptor unknown disease were not significantly different. Neither response nor survival was significantly different between the patients receiving 1 or 4 mg of fadrozole per day. Fadrozole is a well tolerated, effective second line treatment for women with metastatic breast cancer.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Fadrozole hydrochloride, a new nontoxic aromatase inhibitor for the treatment of patients with metastatic breast cancer. 138 48

To evaluate whether a tumour-directed gradient in androgen levels in fatty tissue can account for the maintenance of intra-tissue oestradiol levels, androstenedione (Adione), dehydroepiandrosterone (DHEA), testosterone (Testo) and androstenediol (Adiol) were assayed in breast tumour tissues and in fatty tissue taken at different distances from the tumour. The concentration of Adione was significantly lower in tumour tissue (5.6 +/- 1.5 pmol/g tissue; mean +/- SEM; n = 14) than in the adjacent fatty tissue (20.4 +/- 2.2; P less than 0.005). Testo, by contrast, occurred in equal concentrations in tumour (0.80 +/- 0.11) and in adjacent fatty tissue (0.70 +/- 0.07). Adione levels tended to be lower after the menopause only in fatty tissue, not in the tumour tissue; for Testo no differences were observed between samples from pre- and postmenopausal patients. Tumour DHEA levels (57 +/- 12 pmol/g tissue) were lower than those in fatty tissue (117 +/- 17; P less than 0.02). As with Adione, fatty tissue DHEA concentrations tended to be higher in pre- than in postmenopausal patients. Adiol showed a similar pattern as Testo. For none of the aromatase substrates nor their precursors a tumour-directed gradient was observed. The concentration of Adione in breast cancer tissue is much lower than the reported Km of the aromatase system for Adione. We have concluded, therefore, that the maintenance of oestradiol concentrations in tumour tissues is not substrate-driven.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Tissue androgens and the endocrine autonomy of breast cancer. 138 49

A sensitive in vitro 3H2O microassay for aromatase activity was used to evaluate the potency and selectivity of three aromatase inhibitors in mammalian (gerbil) and avian (ring dove) hypothalamus. The steroidal inhibitors, 1,4,6-androstatrien-3,17-dione (ATD) and 4-hydroxy-androstenedione (4-OH-A) were compared with a new non-steroidal imidazole inhibitor, CGS 16949A [4-(5,6,7,8-tetrahydroimidazo-[1,5-a]-pyridin-5-yl)benzonitrile HCl]. Adult male dove hypothalamic aromatase is highly active [Vmax = 5.3 pmol testosterone (T) converted/h/mg protein], has high substrate binding affinity (Km = 4.0 nM), and direct involvement in control of sexual behaviour. With [1 beta-3H]T or [1 beta-3H]A as substrate, male dove preoptic aromatase activity was inhibited more effectively and selectively by CGS 16949A. Thus, Kis and IC50s for aromatization were approximately 50 times lower for the non-steroidal inhibitor, and inhibition of the other major androgen-metabolizing enzymes (5 alpha/beta-reductase) occurred at concentrations at least one order of magnitude greater than for ATD and 4-OH-A. Neonatal male gerbil hypothalamic aromatase activity (Vmax = 1.3 pmol T converted/h/mg protein) was lower than in the dove. Aromatase inhibition by CGS 16949A is more potent in the neonatal gerbil than in the dove (Kis of 0.03 and 0.60 nM, respectively, with A as substrate). We conclude that the imidazole is an effective aromatase inhibitor in both the adult and developing brain.
J Steroid Biochem Mol Biol 1992 Oct
PMID:In vitro potency and selectivity of the non-steroidal androgen aromatase inhibitor CGS 16949A compared to steroidal inhibitors in the brain. 139 Feb 79

Primates are unique in having adrenals that secrete large amounts of the precursor sex steroids (PSS) dehydroepiandrosterone (DHEA) and especially DHEA-sulfate. The adrenal PSS require the action of 3 beta-hydroxysteroid dehydrogenase/5-ene-4 ene isomerase (3 beta-HSD), 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), 5 alpha-reductase and/or aromatase to form the androgen dihydrotestosterone (DHT) or the estrogens 17 beta-estradiol and androst-5-ene-diol. Knowing the crucial role of 3 beta-HSD and 17 beta-HSD in sex steroid biosynthesis both in classical as well as in peripheral steroidogenic tissues, we have concentrated our efforts on the elucidation of the molecular structure of these enzyme families. We have thus characterized two types of human 3 beta-HSD cDNA clones and their corresponding genes which encode deduced proteins of 371 and 372 amino acids and share 93.5% homology. Human type I 3 beta-HSD is the almost exclusive mRNA species expressed in the placenta and skin, while human type II is the predominant mRNA species in the adrenals, ovaries and testes. We have also recently elucidated the structure of three types of rat 3 beta-HSD cDNAs which all encode a 372 amino acid protein. The predicted rat type I and II 3 beta-HSD proteins expressed adrenals, gonads and adipose tissue share 94% homology while they share 80% similarity with the liver-specific type III 3 beta-HSD. Transient expression of human type I and II as well as rat type I and II 3 beta-HSD cDNAs in HeLa human cervical carcinoma cells reveals that 3 beta-ol dehydrogenase and 5-ene-4-ene isomerase activities reside within a single protein and that these cDNAs encode functional 3 beta-HSD proteins. The expressed rat type III protein possesses a unique property catalyzing selectively the reduction of 3 beta-androstane 5 alpha-steroids such as DHT. Furthermore, we have also demonstrated by site-directed mutagenesis that the lower activity of expressed rat type II compared to rat type I 3 beta-HSD protein is due to a change of four amino acid residues potentially involved in a membrane-spanning domain. In parallel, we have characterized the complete nucleotide sequence of human 17 beta-HSD cDNA clones encoding a 327 amino acid protein as well as two in tandem 17 beta-HSD genes. Two major 17 beta-HSD mRNA species have been detected in several tissues due to a tissue-specific alternative site of initiation of transcription.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1992 Oct
PMID:Ontogeny and subcellular localization of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) in the human and rat adrenal, ovary and testis. 139 Feb 95


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