Aryl Hydrocarbon Receptor-Dependent Induction of Flavin-Containing Monooxygenase mRNAs in Mouse Liver
Aryl Hydrocarbon Receptor-Dependent Induction of Flavin-Containing Monooxygenase mRNAs in Mouse Liver
复制标题
DOI：
10.1124/dmd.108.023457
复制
发表时间：
2008-12-01
影响因子：
3.9
通讯作者：
Okey, Allan B.
中科院分区：
文献类型：
--
作者：
Celius, Trine;Roblin, Steven;Okey, Allan B.
含黄素单加氧酶（FMOs）在解毒过程中起着重要作用，但通常被认为不能被外源药物诱导。我们最近的微阵列研究发现，2,3,7,8-四氯二苯并-对二二英（TCDD）在具有野生型芳烃受体（AHR）的小鼠肝脏中诱导FMO2和FMO3 mrna，而在AHR缺失的小鼠中则没有。本研究的目的是描述FMO调控的机制。在成年雄性小鼠中，FMO3的基础mRNA含量较低，但在4小时和24小时分别诱导6倍和6000倍。FMO2和FMO3的ED50约为1 μ g/kg，与经典ahr调节基因Cyp1a1相似。在成年雌性小鼠中，FMO3 mRNA含量较高，在4 h时未被诱导，但在24 h时升高了8倍。在雄性和雌性成年小鼠中，TCDD均显著下调FMO5 mRNA。幼年小鼠对TCDD的反应无性别差异；TCDD对两性FMO3的诱导作用是前者的4 ~ 6倍。染色质免疫沉淀显示AHR和芳烃核转运蛋白募集到Fmo3调节区域，表明TCDD的诱导是AHR介导的主要事件。虽然TCDD对成年雄性的FMO2和FMO3 mrna具有高度的诱导作用，但总体上FMO的催化活性仅略有增加。与小鼠肝脏中FMO2和FMO3的显著上调相比，TCDD对大鼠肝脏中FMO mRNA的影响较小。然而，FMO2和FMO3 mrna在表达野生型大鼠AHR的转基因小鼠中被高度诱导，这表明大鼠缺乏诱导并不是因为该物种的AHR不合格。
Flavin-containing monooxygenases (FMOs) are important in detoxication but generally are considered not to be inducible by xenobiotics. Our recent microarray studies revealed induction of FMO2 and FMO3 mRNAs by 2,3,7,8-tetrachlorodibenzo-p-dioxin ( TCDD) in liver of mice with wild-type aryl hydrocarbon receptor (AHR) but not in Ahr-null mice. The aim of the present study was to delineate mechanisms of FMO regulation. In adult male mice, basal FMO3 mRNA is low but was induced 6-fold at 4 h and 6000-fold at 24 h. The ED50 was approximately 1 mu g/kg for FMO2 and FMO3, similar to that for the classic AHR-regulated gene, Cyp1a1. In adult female mice basal FMO3 mRNA is high and was not induced at 4 h but was elevated 8-fold at 24 h. FMO5 mRNA was significantly down-regulated by TCDD in both male and female adult mice. Juvenile mice show no sex difference in response to TCDD; FMO3 was induced 4 to 6-fold by TCDD in both sexes. Chromatin immunoprecipitation demonstrated recruitment of AHR and aryl hydrocarbon nuclear translocator proteins to Fmo3 regulatory regions, suggesting that induction by TCDD is a primary AHR-mediated event. Although FMO2 and FMO3 mRNAs were highly induced by TCDD in adult males, overall FMO catalytic activity increased only modestly. In contrast to the striking up-regulation of FMO2 and FMO3 in mouse liver, TCDD has little effect on FMO mRNA in rat liver. However, FMO2 and FMO3 mRNAs were highly induced in transgenic mice that express wild-type rat AHR, indicating that lack of induction in rat is not due to an incompetent AHR in this species.