Alnouti Yazen, Klaassen Curtis D
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA.
J Pharmacol Exp Ther. 2008 Feb;324(2):612-21. doi: 10.1124/jpet.107.129650. Epub 2007 Nov 9.
In the present study, the regulation of the mRNA of 11 sulfotransferases (Sults) and two 3'-phosphoadenosine 5'-phosphosulfate synthase (PAPSs) isozymes by 15 microsomal enzyme inducers (MEI) in livers of male mice and five MEIs in livers of female mice was examined. These MEIs represent the transcriptionally mediated pathways: aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), peroxisomal proliferator-activated receptor alpha (PPARalpha), and NF-E2-related factor 2 (Nrf2). AhR ligands suppress the expression of Sults, especially the Sult1 isoenzymes in female mice. CAR activators up-regulate several Sults and PAPSs2 in female but not in male mice. PXR ligands cause marked induction of Sult1e1 in male, Sult2a1/2a2 in female, and PAPSs2 in both male and female mice. PPARalpha ligands do not have a marked effect on Sult expression in males, but they tend to suppress the expression of several Sult isoforms in female mice. Nrf2 activators appear to induce the mRNA expression of Sults in male and have mixed effects in female mice. In silico analysis indicated the presence of putative binding sites for all five transcription factors in the promoter region of many Sult and PAPSs isoforms. In conclusion, induction of Sults by typical MEIs is not as marked as the induction of P450 enzymes in mice. In addition to gender differences in basal expression of Sults, there is also a marked gender difference in the inducibility of various Sult isoenzymes in mice by MEIs.
在本研究中，检测了15种微粒体酶诱导剂（MEI）对雄性小鼠肝脏中11种磺基转移酶（Sults）和两种3'-磷酸腺苷5'-磷酸硫酸合成酶（PAPSs）同工酶mRNA的调控作用，以及5种MEI对雌性小鼠肝脏的调控作用。这些MEI代表转录介导途径：芳烃受体（AhR）、孕烷X受体（PXR）、组成型雄甾烷受体（CAR）、过氧化物酶体增殖物激活受体α（PPARα）和NF-E2相关因子2（Nrf2）。AhR配体抑制Sults的表达，尤其是雌性小鼠中的Sult1同工酶。CAR激活剂上调雌性小鼠而非雄性小鼠中的几种Sults和PAPSs2。PXR配体在雄性小鼠中显著诱导Sult1e1，在雌性小鼠中诱导Sult2a1/2a2，在雄性和雌性小鼠中均诱导PAPSs2。PPARα配体对雄性小鼠的Sult表达没有显著影响，但它们倾向于抑制雌性小鼠中几种Sult同工型的表达。Nrf2激活剂似乎诱导雄性小鼠中Sults的mRNA表达，在雌性小鼠中则有混合效应。计算机分析表明，许多Sult和PAPSs同工型的启动子区域存在所有五种转录因子的假定结合位点。总之，典型MEI对Sults的诱导作用不如对小鼠中P450酶的诱导作用明显。除了Sults基础表达的性别差异外，MEI对小鼠中各种Sult同工酶的诱导性也存在显著的性别差异。
