The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR)
The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR)
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DOI：
10.1074/jbc.m404949200
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发表时间：
2004-09-10
影响因子：
4.8
通讯作者：
Wojnowski, L
中科院分区：
文献类型：
--
作者：
Burk, O;Koch, I;Wojnowski, L
外源性物质对细胞色素P450 3A（CYP 3A）的诱导可能导致临床相关的药物相互作用。与其他CYP 3A家族成员相比，对CYP 3A 5的诱导研究表明了相互矛盾的结果。我们报告的诱导CYP 3A 5 mRNA在13 16肝细胞制剂暴露于利福平。此外，在暴露于抗生素后，在8个先证者中的3个的肠活检中观察到CYP 3A 5 mRNA的诱导。在CYP 3A 5 *1等位基因携带者的肝细胞和肠中，利福平处理后发现CYP 3A 5转录物的绝对水平最高。对CYP 3A 5诱导机制的阐明表明，组成型激活受体（CAR）和甾烷X受体（PXR）反式激活CYP 3A 5启动子（-688至+49），并且反式激活依赖于间隔6 bp的翻转重复序列（ER 6依赖性）。用原型PXR配体利福平处理导致CYP 3A 5启动子活性的2倍诱导。与这些观察结果一致，PXR和CAR特异性结合ER 6基序。在一组肝脏样本中，肝脏PXR表达与CYP 3A 5 mRNA水平相关。综上所述，本文的研究揭示了位于转录起始位点上游约100 bp的CYP 3A 5启动子中存在功能性ER 6基序，表明CYP 3A 5可通过与CYP 3A 4诱导相似的机制诱导。暴露于诱导剂引起的CYP 3A 5表达增强可能表型复制高表达等位基因CYP 3A 5 *1的作用。以这种方式，CYP 3A 5的诱导可能有助于该P450在药物代谢和药物相互作用中的整体重要性。
Induction of cytochrome P450 3A (CYP3A) by xenobiotics may lead to clinically relevant drug interactions. In contrast with other CYP3A family members, studies on the inducibility of CYP3A5 indicate conflicting results. We report the induction of CYP3A5 mRNA in 13 of 16 hepatocyte preparations exposed to rifampin. Furthermore, induction of CYP3A5 mRNA was observed in intestinal biopsies in three of eight probands following exposure to the antibiotic. The highest absolute levels of CYP3A5 transcripts were found following rifampin treatment in hepatocytes and intestines from carriers of CYP3A5*1 alleles. Elucidation of the mechanism involved in CYP3A5 induction revealed that constitutively activated receptor (CAR) and pregnane X receptor (PXR) transactivated the CYP3A5 promoter (-688 to +49) and that the transactivation was dependent on an everted repeat separated by 6 bp (ER6-dependent). Treatment with the prototypical PXR ligand rifampin led to a 2-fold induction of the CYP3A5 promoter activity. In agreement with these observations, PXR and CAR bound specifically to the ER6 motif. Hepatic expression of PXR correlated with that of CYP3A5 mRNA levels in a bank of liver samples. Taken together, studies here revealed the presence of a functional ER6 motif in the CYP3A5 promoter located -100 bp upstream from the transcription start site, suggesting that CYP3A5 is inducible by mechanisms similar to those involved in CYP3A4 induction. Enhanced expression of CYP3A5 caused by exposure to inducers may phenocopy the effects of the high expression allele CYP3A5*1. In this manner, induction of CYP3A5 may contribute to the overall importance of this P450 in drug metabolism and drug interactions.