Medina-Díaz Irma M, Arteaga-Illán Georgina, de León Mario Bermudez, Cisneros Bulmaro, Sierra-Santoyo Adolfo, Vega Libia, Gonzalez Frank J, Elizondo Guillermo
Toxicology Section, Centro Investigación y Estudios Avazados, Mexico City, D.F. 07000, Mexico.
Drug Metab Dispos. 2007 Jan;35(1):95-102. doi: 10.1124/dmd.106.011759. Epub 2006 Oct 11.
CYP3A4, the predominant cytochrome P450 (P450) expressed in human liver and intestine, contributes to the metabolism of approximately half the drugs in clinical use today. CYP3A4 catalyzes the 6beta-hydroxylation of a number of steroid hormones and is involved in the bioactivation of environmental procarcinogens. The expression of CYP3A4 is affected by several stimuli, including environmental factors such as insecticides and pesticides. The o,p'-1,1,1,-trichloro-2,2-bis (p-chlorophenyl)ethane (DDT) isomer of DDT comprises approximately 20% of technical grade DDT, which is an organochloride pesticide. We have recently shown that o,p'-DDT exposure increases CYP3A4 mRNA levels in HepG2 cells. To determine the mechanism by which o,p'-DDT induces CYP3A4 expression, transactivation and electrophoretic mobility shift assays were carried out, revealing that o,p'-DDT activates the CYP3A4 gene promoter through the pregnane X receptor (PXR). CYP3A4 gene promoter activation resulted in both an increase in CYP3A4 mRNA levels and an increase in the total CYP3A4 activity in HepG2 cells. We also observed induction of CYP3A4 and mouse Cyp3a11 mRNA in the intestine of CYP3A4-transgenic mice after exposure to 1 mg/kg o,p'-DDT. At higher doses, a decrease of CYP3A4 inducibility was observed together with an increase in levels of interleukin 6 mRNA, a proinflammatory cytokine that strongly represses CYP3A4 transcription. The present study indicates that regulation of other genes under PXR control may be altered by o,p'-DDT exposure.
细胞色素P450 3A4（CYP3A4）是在人类肝脏和肠道中表达的主要细胞色素P450（P450），参与了当今临床使用的约一半药物的代谢。CYP3A4催化多种甾体激素的6β-羟基化反应，并参与环境前致癌物的生物活化过程。CYP3A4的表达受到多种刺激的影响，包括杀虫剂和农药等环境因素。滴滴涕（DDT）的邻，对'-1,1,1-三氯-2,2-双（对氯苯基）乙烷异构体约占工业级DDT的20%，它是一种有机氯农药。我们最近发现，暴露于邻，对'-DDT会增加HepG细胞中CYP3A4 mRNA的水平。为了确定邻，对'-DDT诱导CYP3A4表达的机制，我们进行了反式激活和电泳迁移率变动分析，结果表明邻，对'-DDT通过孕烷X受体（PXR）激活CYP3A4基因启动子。CYP3A4基因启动子的激活导致HepG2细胞中CYP3A4 mRNA水平增加以及总CYP3A4活性增强。我们还观察到，CYP3A4转基因小鼠在暴露于1mg/kg邻，对'-DDT后，其肠道中CYP3A4和小鼠Cyp3a11 mRNA被诱导。在较高剂量下，观察到CYP3A4诱导性降低，同时促炎细胞因子白细胞介素6 mRNA水平升高，白细胞介素6强烈抑制CYP3A4转录。本研究表明，暴露于邻，对'-DDT可能会改变PXR调控下的其他基因的表达。
