-
Food and Chemical Toxicology : An... Jun 2019Human placental CYP19A1 catalyzes the estrogen synthesis from androgens. The enzyme is encoded by CYP19A1 gene located in chromosome 15q21. This enzyme is a... (Review)
Review
Human placental CYP19A1 catalyzes the estrogen synthesis from androgens. The enzyme is encoded by CYP19A1 gene located in chromosome 15q21. This enzyme is a monooxygenase in the smooth endoplasmic reticulum. The various promoters of the CYP19A1 gene determine its expression in different tissues and the distal promoter I.1 controls its expression in the placenta and retinoids can regulate the expression. Many food components and environmental chemicals inhibit CYP19A1 activity via different modes of action. These chemicals include gossypol, flavones, flavanones, chalconoids, resveratrol, and tobacco alkaloids derived from foods as well as phthalates, insecticides, fungicides, and biocides in the contaminated foods. The inhibition of placental CYP19A1 could impair pregnancy.
Topics: Aromatase; Aromatase Inhibitors; Environmental Pollutants; Estrogen Receptor Modulators; Female; Food Analysis; Humans; Placenta; Pregnancy; Promoter Regions, Genetic
PubMed: 30922969
DOI: 10.1016/j.fct.2019.03.043 -
Current Topics in Medicinal Chemistry 2022Medicinal plants have a long history of use as food and remedy in traditional and modern societies. They have been used as herbal drugs and sources of novel bioactive... (Review)
Review
Medicinal plants have a long history of use as food and remedy in traditional and modern societies. They have been used as herbal drugs and sources of novel bioactive compounds. They provide a wide array of chemical compounds, many of which can not be synthesized via current synthesis methods. Natural products may provide aromatase inhibitory activity through various pathways and may act clinically effective for treating pathologies associated with excessive aromatase secretion, including breast, ovarian, and endometrial cancers, endometriosis, uterine fibroid, benign prostatic hyperplasia (BPH), prostate cancer, infertility, and gynecomastia. Recent studies have shown that natural products with aromatase inhibitory activity can also be good options against secondary recurrence of breast cancer by exhibiting chemopreventive effects. Therefore, screening for new plant-based aromatase inhibitors may provide novel leads for drug discovery and development, particularly with increased clinical efficacy and decreased side effects.
Topics: Aromatase; Aromatase Inhibitors; Breast Neoplasms; Female; Hormones; Humans; Male; Phytochemicals; Prostatic Hyperplasia
PubMed: 34844542
DOI: 10.2174/1568026621666211129141631 -
Breast Cancer Research and Treatment 1994Extraglandular conversion of C19 steroids to estrogens takes place primarily in the stromal cell compartments of adipose tissue and is catalyzed by aromatase cytochrome... (Review)
Review
Extraglandular conversion of C19 steroids to estrogens takes place primarily in the stromal cell compartments of adipose tissue and is catalyzed by aromatase cytochrome P450 (P450arom, the product of the CYP19 gene). CYP19 gene expression and aromatase activity in breast adipose stromal cells in culture are subject to complex hormonal regulation, which was recently found to be mediated in part by alternative use of tissue-specific promoters of the CYP19 gene. It has been proposed that increased local aromatase activity in breast adipose tissue may influence the growth of breast carcinomas. Using competitive RT-PCR, we quantified P450arom transcripts in breast adipose tissue from mastectomy specimens. In 10 out of 15 patients, the highest transcript levels were found in the quadrant where the tumor was located. We also found the highest proportions of adipose stromal cells vs. adipocytes in these quadrants. These findings suggest that regional differences in the relative proportions of the histologic components give rise to local elevated concentrations of estrogens. Although the initiating events are not known, once a neoplastic change has occurred, tumor growth may be promoted by these locally increased estrogen levels. We are currently investigating alternative promoter use for CYP19 gene transcription to explain this association. Our results underscore the importance of aromatase inhibitors as effective agents in treatment of hormone-responsive breast cancer, since aromatase inhibitors reduce local aromatase activity as well as blood estradiol levels.
Topics: Adipose Tissue; Animals; Aromatase; Breast; Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Promoter Regions, Genetic; Protein Biosynthesis; Transcription, Genetic
PubMed: 7949202
DOI: 10.1007/BF00682738 -
Molecular and Cellular Endocrinology Jul 2002The cytochrome P450 aromatase (P450arom) is the terminal enzyme responsible for the formation of estrogens from androgens. In the rat testis we have immunolocalized the... (Review)
Review
The cytochrome P450 aromatase (P450arom) is the terminal enzyme responsible for the formation of estrogens from androgens. In the rat testis we have immunolocalized the P450arom not only in Leydig cells but also in germ cells and especially in elongated spermatids. Related to the stage of germ cell maturation, we have shown that the level of P450arom transcripts decreases, it is much more abundant in pachytene spermatocytes (PS) than in mature germ cells whereas the aromatase activity is two- to fourfold greater in spermatozoa when compared to younger germ cell preparations. In rat germ cells, the aromatase gene expression is not only under androgen and cyclic AMP control but also subjected to cytokine (TNFalpha) and growth factor (TGFbeta) regulation. In the bank-vole testis we have evidenced a positive correlation between a fully developed spermatogenesis and a strong immunoreactivity for both P450arom and estrogen receptor (ERbeta) not only in Sertoli cells but also in PS and round spermatids (RS). Therefore, the aromatase gene expression and its translation in a fully active protein in rodent germ cells evidence an additional site for estrogen production within the testis. Our recent data showing that human ejaculated spermatozoa expressed specific transcripts for P450arom reinforced the observations reported in germ cells of other mammalian species. Together with the widespread distribution of ERs in testicular cells these data bring enlightenment on the hormonal regulation of spermatogenesis.
Topics: Animals; Aromatase; Estrogens; Gene Expression Regulation; Germ Cells; Humans; Leydig Cells; Male; Spermatogenesis; Testis
PubMed: 12161013
DOI: 10.1016/s0303-7207(02)00107-7 -
Fertility and Sterility Sep 2016
Topics: Aromatase; Aromatase Inhibitors; Humans; Inflammation; MicroRNAs; Obesity
PubMed: 27473353
DOI: 10.1016/j.fertnstert.2016.06.045 -
International Journal of Fertility and... 1994Extraglandular conversion of C19 steroids to estrogens takes place primarily in the stromal cell component of adipose tissue and is catalyzed by aromatase cytochrome... (Review)
Review
Extraglandular conversion of C19 steroids to estrogens takes place primarily in the stromal cell component of adipose tissue and is catalyzed by aromatase cytochrome P450 (P450arom; the product of the CYP19 gene). CYP19 gene expression and aromatase activity in breast adipose stromal cells in culture are subject to complex hormonal regulation, which was recently found to be mediated in part by alternative use of tissue-specific promoters of the CYP19 gene. It has been proposed that increased local aromatase activity in breast adipose tissue may influence the growth of breast carcinomas. Using competitive RT-PCR, we quantified P450arom transcripts in breast adipose tissue from mastectomy specimens. In 10/15 patients, highest transcript levels were found in the quadrant where the tumor was located. We also found the highest proportions of adipose stromal cells versus adipocytes in those quadrants. Such findings suggest that regional differences in the relative proportions of the various histologic components give rise to locally elevated concentrations of estrogens. Although the initiating events are not known, once a neoplastic change has occurred, tumor growth may be promoted by the locally increased estrogen levels. We are currently investigating alternative promoter use for CYP19 gene transcription to explain this association. Our results underscore the importance of aromatase inhibitors as effective agents in treatment of hormone-responsive breast cancer, since aromatase inhibitors reduce local aromatase activity as well as blood estradiol levels.
Topics: Adipose Tissue; Aromatase; Breast Neoplasms; Estrogens; Female; Gene Expression Regulation, Enzymologic; Genes; Humans; Promoter Regions, Genetic
PubMed: 7874190
DOI: No ID Found -
Endocrine Reviews Jun 1994
Review
Topics: Amino Acid Sequence; Animals; Aromatase; Base Sequence; Estrogens; Gene Expression; Humans; Isoenzymes; Molecular Sequence Data
PubMed: 8076586
DOI: 10.1210/edrv-15-3-342 -
Seminars in Reproductive Medicine 2000Our knowledge of the physiologic roles of estrogen in women and men has been advanced by recent descriptions of mutations disrupting estrogen biosynthesis and action.... (Review)
Review
Our knowledge of the physiologic roles of estrogen in women and men has been advanced by recent descriptions of mutations disrupting estrogen biosynthesis and action. Aromatase deficiency results from autosomal recessive inheritance of mutations in the CYP19 gene. It gives rise to ambiguous genitalia in 46,XX individuals. At puberty, affected girls have hypergonadotropic hypogonadism, fail to develop secondary sexual characteristics, and exhibit progressive virilization. The affected 46,XY individuals have normal male sexual differentiation and pubertal maturation. These men are extremely tall and have eunuchoid proportions with continued linear growth into adulthood, lack of epiphyseal closure, and osteoporosis due to estrogen deficiency. Although estrogen was shown to be essential for normal sperm production and function in mice, its role in fertility is not clear in men. Thus far, one estrogen-resistant human, a man with a mutant estrogen receptor-alpha gene, has been described. His clinical presentation was similar to that of aromatase-deficient men.
Topics: Animals; Aromatase; Drug Resistance; Estrogen Replacement Therapy; Estrogens; Female; Humans; Hypogonadism; Male; Models, Animal; Mutation; Osteoporosis; Puberty; Virilism
PubMed: 11305285
DOI: 10.1055/s-2000-13481 -
The Journal of Steroid Biochemistry and... 2007Aromatase is a key enzyme of estrogen production through conversion from serum androgens in estrogen-dependent postmenopausal breast cancer. Aromatase has been reported... (Review)
Review
Aromatase is a key enzyme of estrogen production through conversion from serum androgens in estrogen-dependent postmenopausal breast cancer. Aromatase has been reported to be predominantly located in intratumoral stromal cells and adipocytes but not in parenchymal or carcinoma cells in breast cancer tissue. It is, however, true that there have been controversies regarding intratumoral localization of aromatase in human breast carcinoma, especially whether intratumoral production of estrogens through aromatase occurs in parenchymal or stromal cells. Results of several studies suggested that aromatase present in parenchymal carcinoma cells plays more important roles in the growth and invasion of breast carcinomas than that in stromal cells through providing higher levels of estrogens to carcinoma cells. Aromatase inhibitors are increasingly being used in place of tamoxifen after results of various clinical trials demonstrated that aromatase inhibitors are more effective in increasing survival and recurrence of estrogen-dependent breast cancer patients. Therefore, it is important to clarify the estrogen supplying pathway by aromatase inside of breast carcinoma tissues in order to evaluate the possible efficacy of aromatase inhibitor treatment. In this review, the controversies regarding these intratumoral localization patterns in human breast carcinoma will be briefly summarized.
Topics: Animals; Aromatase; Breast Neoplasms; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Protein Transport; Stromal Cells
PubMed: 17624762
DOI: 10.1016/j.jsbmb.2007.05.007 -
The Journal of Steroid Biochemistry and... Mar 1993Site-directed mutagenesis experiments have been carried out to determine the structure-function relationship of human aromatase. By sequence comparison, the region in... (Review)
Review
Site-directed mutagenesis experiments have been carried out to determine the structure-function relationship of human aromatase. By sequence comparison, the region in aromatase that corresponds to the distal helix of cytochrome P-450cam has been identified to be Gln-298 to Val-313. Eight aromatase mutants with changes in this region, i.e. C299A, E302L, P308F, D309N, D309A, T310S, T310C, and S312C, have been generated using a mammalian cell stable-expression system. The results from site-directed mutagenesis studies indicate that the region containing Gln-298 to Val-313 is indeed a very important part of the active site of aromatase. The catalytic properties of P308F, D309N, and D309A have been examined in detail and are discussed. Active site-directed labeling is also an important approach to investigate the structure-function relationship of aromatase. HPLC-linked electrospray mass spectrometry is indicated as a useful technique for the characterization of active site-directed probe-modified enzyme. The mass spectral analysis of aromatase suggests that aromatase is glycosylated.
Topics: Amino Acid Sequence; Animals; Aromatase; Binding Sites; Cell Line; Humans; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Protein Structure, Secondary; Sequence Homology, Amino Acid; Transfection
PubMed: 8476748
DOI: 10.1016/0960-0760(93)90238-r