RESUMO
Endometriosis is a debilitating disease in which apoptotic, genetic, immunological, angiogenic and environmental factors have been implicated. Endocrine-disrupting agents (e.g. dioxins) might be involved. Dioxins, via the arylhydrocarbon receptor (AhR), induce estrogen-metabolizing enzymes CYP1A1 and CYP1B1. Elevated expression of gamma-SYNUCLEIN (gamma-SYN) has been associated with hormone-related conditions. Tissue sets consisting of eutopic and ectopic (ovarian) endometrium from patients with stage 3 or 4 endometriosis were obtained. Following RNA extraction and reverse transcription, quantitative real-time reverse transcriptase-polymerase chain reaction was performed for anti-apoptotic B-cell leukaemia/lymphoma 2 (BCL-2), CYP1A1, CYP1B1, estrogen receptor (ER)alpha, ER beta and gamma-SYN. Immunohistochemical analyses for gamma-syn, ER alpha, ER beta and CYP1A1 were also conducted. A 3-9-fold increase in intra-individual expression of CYP1A1 in ectopic (ovarian) endometrium compared with eutopic tissue was observed; immunohistochemical analyses pointed to CYP1A1 being localized to the glandular epithelium. This intra-individual expression profile was not observed for CYP1B1 or BCL-2. However, a 5-53-fold intra-individual increase in gamma-SYN expression was also demonstrated in six of nine tissue sets (a further two showed an increase that was not considered significant) when comparing ectopic to eutopic endometrium; gamma-syn positivity was associated with endothelial cells. An elevation in ER beta was also noted when comparing ectopic to eutopic endometrium; with regard to ER alpha, this was inconsistent. These results suggest an up-regulation of dioxin-inducible CYP1A1 and gamma-SYN occurs in endometriosis. Whether gamma-syn may be a novel diagnostic marker for endometriosis remains to be ascertained.
Assuntos
Citocromo P-450 CYP1A1/metabolismo , Endometriose/metabolismo , Endométrio/metabolismo , Regulação da Expressão Gênica/genética , gama-Sinucleína/metabolismo , Adulto , Hidrocarboneto de Aril Hidroxilases , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1 , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Endometriose/genética , Endometriose/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/genética , gama-Sinucleína/genéticaRESUMO
Tamoxifen has been used in the management of receptor-positive breast cancer for >20 years. Usage confers an elevated risk of developing endometrial carcinoma. Its mechanism of carcinogenicity remains unresolved with controversy as to whether or not this is mediated through a genotoxic mechanism. Usage is not only associated with an elevated occurrence of endometrioid endometrial carcinoma, but also type 2 and mixed epithelial-stromal tumours (MESTs) that have a poorer prognosis. Following hysterectomy, endometrial tissues (n=18) classified as benign (n=6), non-tamoxifen-associated carcinoma (n=6) and tamoxifen-associated carcinoma (n=6) were obtained; quantitative gene expression was performed. Employing real-time RT-PCR, the relative gene expressions of phase I/II metabolic enzymes CYP1A2, CYP1B1 and CYP3A4, cathechol-O-methyltransferase (COMT) and SULT2A1 were ascertained. Measurable mRNA transcripts, especially for those genes associated with tamoxifen bioactivation, were quantifiable in all the tissues examined. Whether this is evidence that generation of genotoxic tamoxifen metabolites may occur in human endometrial tissue remains to be ascertained.
Assuntos
Antineoplásicos Hormonais/farmacocinética , Carcinoma/enzimologia , Sistema Enzimático do Citocromo P-450/genética , Neoplasias do Endométrio/enzimologia , Endométrio/enzimologia , RNA Mensageiro/metabolismo , Tamoxifeno/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biotransformação , Carcinoma/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Neoplasias do Endométrio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Sulfotransferases/genética , Sulfotransferases/metabolismoRESUMO
OBJECTIVE: To provide an overview of the epidemiology, etiology, pathogenesis, diagnosis, and management of intrahepatic cholestasis of pregnancy. METHODS: We searched the Medline and PubMed database using the key words intrahepatic cholestasis of pregnancy, obstetric cholestasis, diagnosis, management, and complications. RESULTS: Intrahepatic cholestasis of pregnancy, or obstetric cholestasis, is a liver condition that develops during pregnancy. It is associated with increased perinatal morbidity and mortality. Pruritus and risk of postpartum hemorrhage are the main causes of maternal morbidity. Intrahepatic cholestasis of pregnancy is a diagnosis of exclusion. The current management policies depend on regular fetal and maternal monitoring and delivery at fetal maturity. The analysis of the quality of previous studies provided in this review highlights the areas of deficiency in evidence-based knowledge of this subject. CONCLUSIONS: More research is required into the etiology, pathogenesis, and monitoring modalities that can specifically predict fetal outcome in intrahepatic cholestasis of pregnancy. Clinical trials are required to identify the most suitable drugs for treatment.