Expression profiles of drug-metabolizing enzyme CYP3A and drug efflux transporter multidrug resistance 1 subfamily mRNAs in rat small intestine
Expression profiles of drug-metabolizing enzyme CYP3A and drug efflux transporter multidrug resistance 1 subfamily mRNAs in rat small intestine
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DOI：
10.1124/dmd.31.10.1235
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发表时间：
2003-10-01
影响因子：
3.9
通讯作者：
Yokoyama, T
中科院分区：
文献类型：
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作者：
Takara, K;Ohnishi, N;Yokoyama, T
本研究的目的是使用逆转录-聚合酶链反应（PCR）检测CYP 3A 1，CYP 3A 2，CYP 3A 9和CYP 3A 18 mRNA以及多药耐药（mdr）1a和mdr 1b mRNA在正常雄性Wistar大鼠肝脏和小肠中的表达谱。在大鼠肝脏中，很容易检测到CYP 3A 1、CYP 3A 2和CYP 3A 18的PCR产物，而CYP 3A 9的PCR产物很少，几乎未检测到mdr 1a和mdr 1b。令人惊讶的是，在小肠中未检测到CYP 3A 1和CYP 3A 2的PCR产物，但很容易检测到CYP 3A 9、CYP 3A 18和mdr 1a的PCR产物，还观察到mdr 1b的微弱条带。发现CYP 3A 9和CYP 3A 18水平在十二指肠中较高，从肠道顶部到底部降低，表明小肠中CYP 3A 9和CYP 3A 18表达存在区域差异。相反，mdr 1a的表达从上肠到下肠逐渐增加。因此，提示正常大鼠小肠中的药物代谢是由CYP 3A 9和CYP 3A 18介导的，而不是CYP 3A 1和CYP 3A 2。此外，CYP 3A 9，CYP 3A 18和mdr 1a表达的区域差异在小肠中发现。CYP 3A 9和CYP 3A 18的分布与mdr 1a的分布不同，提示药物清除途径的协同作用。这些信息对于基于大鼠离体和体内研究的药物代谢研究是重要的。
The purpose of this study is to examine the expression profiles of CYP3A1, CYP3A2, CYP3A9, and CYP3A18 mRNAs as well as multidrug resistance (mdr)1a and mdr1b mRNAs in the liver and small intestine of normal male Wistar rats using a reverse transcription-polymerase chain reaction (PCR). In the rat liver, the PCR products for CYP3A1, CYP3A2, and CYP3A18 were readily detectable, whereas CYP3A9 was slightly and mdr1a and mdr1b barely detected. Surprisingly, no PCR products for CYP3A1 and CYP3A2 were detected in the small intestine, but those for CYP3A9, CYP3A18, and mdr1a were readily detectable, and a faint band for mdr1b was also observed. Both CYP3A9 and CYP3A18 levels were found to be high in the duodenum and decreased from the top to bottom of the gut, indicating regional differences in both CYP3A9 and CYP3A18 expression in the small intestine. In contrast, mdr1a expression increased gradually from the upper to lower intestine. Consequently, it was suggested that drug metabolism in the small intestine of normal rats was mediated by CYP3A9 and CYP3A18 rather than CYP3A1 and CYP3A2. Also, regional differences of CYP3A9, CYP3A18, and mdr1a expression were found in the small intestine. The distributions of CYP3A9 and CYP3A18 were different from the distribution of mdr1a, suggesting the cooperative action of drug clearance pathways. This information is important to drug metabolism research based on ex vivo and in vivo studies using rats.