Nuclear receptor, pregnane X receptor, is required for induction of UDP-glucuronosyltransferases in mouse liver by pregnenolone-16α-carbonitrile
Nuclear receptor, pregnane X receptor, is required for induction of UDP-glucuronosyltransferases in mouse liver by pregnenolone-16α-carbonitrile
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DOI：
10.1124/dmd.31.7.908
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发表时间：
2003-07-01
影响因子：
3.9
通讯作者：
Klaassen, CD
中科院分区：
文献类型：
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作者：
Chen, C;Staudinger, JL;Klaassen, CD
本研究的目的是确定在UDP-葡萄糖醛酸基转移酶（UGT）的诱导作用，双烯醇酮-16 α-甲腈（PCN）的藜芦烷X受体（PXR）。4至6个月大的雄性野生型和PXR基因缺失小鼠接受对照或PCN处理（1500 ppm）饮食21天。在第22天，取肝脏制备微粒体和总RNA，以分别测定UGT活性和mRNA水平。在野生型小鼠，PCN治疗显着增加UGT活动对胆红素，1-萘酚，氯霉素，甲状腺素，和三碘甲状腺原氨酸。在对照饮食中，PXR基因敲除小鼠对上述底物（1-萘酚除外）的UGT活性显著高于野生型小鼠。然而，在PXR-null小鼠的UGT活性不增加PCN。与上述结果一致，参与胆红素和酚类化合物葡萄糖醛酸化的小鼠Ugt 1a 1和Ugt 1a 9的mRNA水平在PCN治疗后野生型小鼠中增加约100%，而Ugt 1a 2，1a 6和2b 5的表达不受影响。相反，PCN治疗对PXR缺失小鼠中这些UGT的mRNA水平没有影响。总之，这些结果表明，PCN处理诱导小鼠肝脏中的葡萄糖醛酸化，PXR调节一些UGT的组成型和PCN诱导型表达。
The aim of this study was to determine the role of pregnane X receptor (PXR) in the induction of UDP-glucuronosyltransferases (UGTs) by pregnenolone-16alpha-carbonitrile (PCN). Four- to six-month-old male wild-type and PXR-null mice received control or PCN-treated (1500 ppm) diet for 21 days. On day 22, livers were taken to prepare microsomes and total RNA to determine UGT activity and mRNA levels, respectively. In wild-type mice, PCN treatment significantly increased UGT activities toward bilirubin, 1-naphthol, chloramphenicol, thyroxine, and triiodothyronine. On control diet, the UGT activities toward the above substrates (except for 1-naphthol) in the PXR-null mice were significantly higher than those of wild-type mice. However, UGT activities in PXR-null mice were not increased by PCN. In agreement with the above findings, mRNA levels of mouse Ugt1a1 and Ugt1a9, which are involved in the glucuronidation of bilirubin and phenolic compounds, were increased about 100% in wild-type mice following PCN treatment, whereas the expression of Ugt1a2, 1a6, and 2b5 was not affected. In contrast, PCN treatment had no effect on the mRNA levels of these UGTs in PXR-null mice. Taken together, these results indicate that PCN treatment induces glucuronidation in mouse liver, and that PXR regulates constitutive and PCN-inducible expression of some UGTs.