RESUMO
Estrogens are important factors in the development of endometriosis, and can induce cell proliferation and stimulate cell division. COMT constitutes a crucial element in estrogen metabolism and has been suggested to be involved in the development of endometriosis. This study had the objective of to determine whether the presence of COMT val/met polymorphism (rs4680) increases the risk to endometriosis in infertile patients. A case-control study that included 198 infertile women with endometriosis, 71 infertile women without endometriosis, and 168 fertile women as control group of the Faculdade de Medicina do ABC. COMT (val/met) genotypes were identified by real time PCR (genotyping TaqMan assay) and the results were analyzed statistically by χ² test. The data showed no statistical difference in the distribution of COMT genotypes neither between infertile patients with endometriosis and control group (p = 0.567), regardless disease degree, nor between infertile patients without endometriosis and control group (p = 0.460). In conclusion, the COMT val/met polymorphism is not associated to endometriosis-related infertility in the Brazilian population evaluated. However, more studies in larger populations are necessary to confirm these results.
Assuntos
Catecol O-Metiltransferase/genética , Endometriose/complicações , Infertilidade Feminina/genética , Polimorfismo de Nucleotídeo Único/fisiologia , Doenças Uterinas/complicações , Adulto , Brasil , Estudos de Casos e Controles , Catecol O-Metiltransferase/fisiologia , Endometriose/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Infertilidade Feminina/etiologia , Desequilíbrio de Ligação , Fatores de Risco , Índice de Gravidade de Doença , Doenças Uterinas/genéticaRESUMO
BACKGROUND: Data suggest that estrogen-metabolizing genes may be involved in breast cancer carcinogenesis. OBJECTIVE: The aim of this study was to determine the association of CYP1A1 and COMT polymorphisms with this disease. MATERIAL AND METHODS: A pilot case-control study was conducted with Mexican women. Ninety-one breast cancer patients and 94 healthy controls were selected. Epidemiological and clinical questionnaires were answered by all participants, and genotyping data were obtained. CYP1A1 3801 T>C (rs4646903), CYP1A1 4889 A>G (rs1048943) and COMT 1947 G>A (rs4680) polymorphisms were analyzed by PCR-RFLP. RESULTS: The results showed a high risk of breast cancer in women carrying the CYP1A1 (3801 T>C) m2/m2 genotype (OR=2.52; 95%CI=1.04-6.08). The risk was higher in postmenopausal women (OR=3.38; 95%CI=1.05-10.87). No association between COMT 1947 G>A (rs4680) or CYP1A1 4889 A>G (rs1048943) and breast cancer was found. CONCLUSIONS: This study suggests that the CYP1A1 (3801 T>C) m2/m2 genotype may contribute to breast cancer susceptibility in Mexican women.
Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Catecol O-Metiltransferase/genética , Citocromo P-450 CYP1A1/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Neoplasias da Mama/enzimologia , Neoplasias da Mama/epidemiologia , Carcinoma Ductal de Mama/enzimologia , Carcinoma Ductal de Mama/epidemiologia , Catecol O-Metiltransferase/fisiologia , Anticoncepcionais Femininos/efeitos adversos , Citocromo P-450 CYP1A1/fisiologia , Estrogênios/metabolismo , Estrogênios/uso terapêutico , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , México/epidemiologia , Pessoa de Meia-Idade , Proteínas de Neoplasias/fisiologia , Neoplasias Hormônio-Dependentes/enzimologia , Neoplasias Hormônio-Dependentes/epidemiologia , Neoplasias Hormônio-Dependentes/genética , Projetos Piloto , Pós-Menopausa , História Reprodutiva , Risco , Fumar/epidemiologiaRESUMO
Estradiol (E(2)) accelerates oviductal egg transport through intraoviductal nongenomic pathways in cyclic rats and through genomic pathways in pregnant rats. This shift in pathways, which we have provisionally designated as intracellular path shifting (IPS), is caused by mating-associated signals and represents a novel and hitherto unrecognized phenomenon. The mechanism underlying IPS is currently under investigation. Using microarray analysis, we identified several genes the expression levels of which changed in the rat oviduct within 6 hours of mating. Among these genes, the mRNA level for the enzyme catechol-O-methyltransferase (COMT), which produces methoxyestradiols from hydroxyestradiols, decreased 6-fold, as confirmed by real-time PCR. O-methylation of 2-hydroxyestradiol was up to 4-fold higher in oviductal protein extracts from cyclic rats than from pregnant rats and was blocked by OR486, which is a selective inhibitor of COMT. The levels in the rat oviduct of mRNA and protein for cytochrome P450 isoforms 1A1 and 1B1, which form hydroxyestradiols, were detected by RT-PCR and Western blotting. We explored whether methoxyestradiols participate in the pathways involved in E(2)-accelerated egg transport. Intrabursal application of OR486 prevented E(2) from accelerating egg transport in cyclic rats but not in pregnant rats, whereas 2-methoxyestradiol (2ME) and 4-methoxyestradiol mimicked the effect of E(2) on egg transport in cyclic rats but not in pregnant rats. The effect of 2ME on egg transport was blocked by intrabursal administration of the protein kinase inhibitor H-89 or the antiestrogen ICI 182780, but not by actinomycin D or OR486. We conclude that in the absence of mating, COMT-mediated formation of methoxyestradiols in the oviduct is essential for the nongenomic pathway through which E(2) accelerates egg transport in the rat oviduct. Yet unidentified mating-associated signals, which act directly on oviductal cells, shut down the E(2) nongenomic signaling pathway upstream and downstream of methoxyestradiols. These findings highlight a physiological role for methoxyestradiols in the female genital tract, thereby confirming the occurrence of and providing a partial explanation for the mechanism underlying IPS.