Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA
Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA
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DOI：
10.1124/dmd.30.10.1108
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发表时间：
2002-10-01
影响因子：
3.9
通讯作者：
Wojnowski, L
中科院分区：
文献类型：
--
作者：
Koch, I;Weil, R;Wojnowski, L
4个CYP 3A基因对整体CYP 3A活性的单独贡献的阐明受到其序列和功能相似性的阻碍。我们使用基因特异性TaqMan探针研究了CYP 3A mRNA在肝脏和其他各种组织中的表达。CYP 3A 4转录物是检测的63个白色欧洲肝脏中最丰富的CYP 3A mRNA，平均占合并CYP 3A mRNA库的95%。CYP 3A 5和CYP 3A 7各自平均贡献2%，而CYP 3A 43贡献0.3%的转录本。14%的肝脏表现出CYP 3A 5转录物的比例增加（范围4-20%）。这些肝脏要么是CYP 3A 5多态性标记物（CYP 3A 5 *1A等位基因）杂合，要么表达极低水平的CYP 3A 4 mRNA。CYP 3A 7的表达呈双峰型，15%的肝细胞CYP 3A 7表达增加。CYP 3A 4是肠道中的主要CYP 3A，其次是CYP 3A 5。CYP 3A 5和CYP 3A 7也在肾上腺和前列腺中表达，但不表达CYP 3A 4，而在肾脏中仅检测到CYP 3A 5。这三种组织中的胆甾烷X受体mRNA表达水平远低于肠道，表明可能存在不同的CYP 3A表达调节模式。外周血淋巴细胞中未检测到CYP 3A基因的表达。总之，这些试验和结果应有助于我们进一步剖析CYP 3A同工酶的调节和生理药理学意义。
The elucidation of the individual contributions of the four CYP3A genes to the overall CYP3A activity has been hampered by similarities in their sequence and function. We investigated the expression of CYP3A mRNA species in the liver and in various other tissues using gene-specific TaqMan probes. CYP3A4 transcripts were the most abundant CYP3A mRNA in each of the 63 white European livers tested and accounted on average for 95% of the combined CYP3A mRNA pool. CYP3A5 and CYP3A7 each contributed on average 2%, whereas CYP3A43 contributed 0.3% transcripts to this pool. Fourteen percent of livers exhibited an increased share of CYP3A5 transcripts (range 4-20%). These livers were either heterozygous for the marker of the CYP3A5 polymorphism, the CYP3A5*1A allele, or expressed very low levels of CYP3A4 mRNA. The CYP3A7 expression was bimodal, and it was increased in 15% livers. CYP3A4 was the dominant CYP3A in the intestine, followed by CYP3A5. CYP3A5 and CYP3A7, but not CYP3A4, were also expressed in the adrenal gland and in the prostate, whereas only CYP3A5 was detected in the kidney. These three tissues were shown to express much lower levels of pregnane X receptor mRNA than the intestine, indicating possibly a different mode of regulation of CYP3A expression. Expression of CYP3A genes was undetectable in peripheral blood lymphocytes. In summary, these assays and results should aid in our efforts to further dissect the regulation and the physiological and pharmacological significance of CYP3A isozymes.