Medina-Díaz I M, Estrada-Muñiz E, Reyes-Hernández O D, Ramírez P, Vega L, Elizondo G
Universidad Autónoma de Nayarit, Nayarit, México.
Toxicol Appl Pharmacol. 2009 Sep 1;239(2):162-8. doi: 10.1016/j.taap.2008.11.009. Epub 2008 Nov 24.
Arsenic is an environmental pollutant that has been associated with an increased risk for the development of cancer and several other diseases through alterations of cellular homeostasis and hepatic function. Cytochrome P450 (P450) modification may be one of the factors contributing to these disorders. Several reports have established that exposure to arsenite modifies P450 expression by decreasing or increasing mRNA and protein levels. Cytochrome P450 3A4 (CYP3A4), the predominant P450 expressed in the human liver and intestines, which is regulated mainly by the Pregnane X Receptor-Retinoid X Receptor alpha (PXR-RXR alpha) heterodimer, contributes to the metabolism of approximately half the drugs in clinical use today. The present study investigates the effect of sodium arsenite and its metabolites monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) on CYP3A4, PXR, and RXR alpha expression in the small intestine of CYP3A4 transgenic mice. Sodium arsenite treatment increases mRNA, protein and CYP3A4 activity in a dose-dependent manner. However, the increase in protein expression was not as marked as compared to the increase in mRNA levels. Arsenite treatment induces the accumulation of Ub-protein conjugates, indicating that the activation of this mechanism may explain the differences observed between the mRNA and protein expression of CYP3A4 induction. Treatment with 0.05 mg/kg of DMA(III) induces CYP3A4 in a similar way, while treatment with 0.05 mg/kg of MMA(III) increases mostly mRNA, and to a lesser degree, CYP3A4 activity. Sodium arsenite and both its metabolites increase PXR mRNA, while only DMA(III) induces RXR alpha expression. Overall, these results suggest that sodium arsenite and its metabolites induce CYP3A4 expression by increasing PXR expression in the small intestine of CYP3A4 transgenic mice.
砷是一种环境污染物，通过改变细胞内稳态和肝功能，与癌症及其他多种疾病的发生风险增加有关。细胞色素P450（P450）修饰可能是导致这些疾病的因素之一。多项报告证实，接触亚砷酸盐会通过降低或增加mRNA和蛋白质水平来改变P450表达。细胞色素P450 3A4（CYP3A4）是在人类肝脏和肠道中表达的主要P450，主要由孕烷X受体-视黄酸X受体α（PXR-RXRα）异二聚体调控，参与了当今临床使用的约一半药物的代谢。本研究调查了亚砷酸钠及其代谢产物一甲基亚砷酸（MMA(III)）和二甲基亚砷酸（DMA(III)）对CYP3A4转基因小鼠小肠中CYP3A4、PXR和RXRα表达的影响。亚砷酸钠处理以剂量依赖方式增加mRNA、蛋白质和CYP3A4活性。然而，与mRNA水平的增加相比，蛋白质表达的增加并不明显。亚砷酸盐处理诱导了泛素-蛋白质缀合物的积累，表明该机制的激活可能解释了CYP3A4诱导的mRNA和蛋白质表达之间观察到的差异。用0.05 mg/kg的DMA(III)处理以类似方式诱导CYP3A4，而用0.05 mg/kg的MMA(III)处理主要增加mRNA，且在较小程度上增加CYP3A4活性。亚砷酸钠及其两种代谢产物均增加PXR mRNA，而只有DMA(III)诱导RXRα表达。总体而言，这些结果表明，亚砷酸钠及其代谢产物通过增加CYP3A4转基因小鼠小肠中的PXR表达来诱导CYP3A4表达。
