Effect of retinoids on UDP-glucuronosyltransferase 2B7 mRNA expression in Caco-2 cells.
Effect of retinoids on UDP-glucuronosyltransferase 2B7 mRNA expression in Caco-2 cells.
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DOI：
10.2133/dmpk.23.364
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发表时间：
2008
影响因子：
2.1
通讯作者：
Yuan Lu;S. Bratton;J. Heydel;A. Radomińska-Pandya
中科院分区：
文献类型：
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作者：
Yuan Lu;S. Bratton;J. Heydel;A. Radomińska-Pandya
人UDP-葡萄糖醛酸基转移酶2B 7（UGT 2B 7）是参与内源性化合物和外源性物质葡萄糖醛酸化的主要亚型之一。该亚型是唯一显示葡萄糖醛酸类视色素及其氧化衍生物的人UGT。在这项研究中，全反式维甲酸（atRA），9-顺式RA，和RAR激动剂TTNPB，对UGT 2B 7和UGT 2B 15在Caco-2细胞的mRNA表达的影响进行了检查。这些类维生素A均以浓度依赖性方式显著抑制UGT 2B 7 mRNA表达，IC 50值分别为3.5、0.3和0.2 μ M。然而，当其他两种UGT（UGT 2B 15或-1A6）暴露于atRA、9-cis RA或TTNPB时，未观察到抑制作用，表明类维生素A的抑制作用可能对UGT 2B 7亚型具有特异性。此外，氧化atRA衍生物、4-OH-atRA、4-氧代-atRA和5，6-环氧-atRA的实验表明，这些RA降解产物对UGT 2B 7 mRNA表达没有抑制作用。这些数据使我们假设RA的生物活性形式抑制肠细胞中UGT 2B 7的表达。这一信息提供了一种新的途径，当类维生素A以药理学浓度在体内积累时，通过下调参与其生物转化为可溶性衍生物的酶，类维生素A可能会增强其自身的毒性。
Human UDP-glucuronosyltransferase 2B7 (UGT2B7) is one of the major isoforms involved in the glucuronidation of endogenous compounds and xenobiotics. This isoform is the only human UGT shown to glucuronidate retinoids and their oxidized derivatives. In this study, the effects of all-trans retinoic acid (atRA), 9-cis RA, and the RAR agonist TTNPB, on UGT2B7 and UGT2B15 mRNA expression in Caco-2 cells have been examined. Each of these retinoids significantly suppressed UGT2B7 mRNA expression in a concentration-dependent manner with IC50 values of 3.5, 0.3, and 0.2 microM, respectively. However, no inhibition was observed when two other UGTs, UGT2B15 or -1A6, were exposed to atRA, 9-cis RA, or TTNPB, demonstrating that the inhibitory effect of retinoids might be specific for the UGT2B7 isoform. Further, experiments with oxidized atRA derivatives, 4-OH-atRA, 4-oxo-atRA, and 5,6-epoxy-atRA showed that these RA degradation products have no inhibitory effect on UGT2B7 mRNA expression. These data lead us to hypothesize that biologically active forms of RA suppress the expression of UGT2B7 in intestinal cells. This information provides a new pathway by which retinoids may enhance their own toxicity when accumulated in the body at pharmacological concentrations by down-regulating the enzymes involved in their biotransformation into soluble derivatives.