Significant change of cytochrome P450s activities in patients with hepatocellular carcinoma.
Significant change of cytochrome P450s activities in patients with hepatocellular carcinoma.
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肝细胞癌患者细胞色素P450s活性的显着变化。
DOI：
10.18632/oncotarget.9437
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发表时间：
2016-08-02
期刊：
影响因子：
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通讯作者：
Qiao HL
中科院分区：
文献类型：
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作者：
Zhou J;Wen Q;Li SF;Zhang YF;Gao N;Tian X;Fang Y;Gao J;Cui MZ;He XP;Jia LJ;Jin H;Qiao HL
缺乏有关药物代谢酶个体差异的信息是为肝细胞癌（HCC）患者设计个性化药物治疗方法的最重要障碍之一。为了评估细胞色素P450（CYP）在HCC环境中内源性和外源性分子代谢中的作用，研究了105份正常和102份HCC肝组织样本微粒体中10种主要CYP的活性变化。我们发现，肝癌患者和对照组之间的固有清除率（克林特）表示的β-内酰胺酶活性值不同。与对照组相比，HCC患者样本显示CYP 2C 9、CYP 2D 6和CYP 2 E1的克林特增加。同时，与对照组相比，CYP 1A 2、CYP 2C 8和CYP 2C 19克林特值降低，CYP 2A 6、CYP 2B 6和CYP 3A 4/5活性无变化。对于伴有肝纤维化或肝硬化的HCC患者，除了CYP 2D 6在伴有肝硬化的HCC患者中具有更高的值之外，对于CYP 2D 6亚型观察到相同的活性变化。CYP 2D 6 *10（100 C>T）、CYP 2C 9 *3（42614 A>C）和CYP 3A 5 *3（6986 A>G）多态性对酶活性有一定的影响。在HCC组中，与野生型样本相比，CYP 2D 6 *10突变纯合子的克林特降低了95%，并且该纯合子的频率比对照低2.8倍。总之，HCC患者中β亚型的活性受到不同的影响。某些代谢酶的遗传多态性，特别是CYP 2D 6 *10，可能影响酶的活性。CYP 2D 6 *10等位基因频率在HCC患者和对照组之间存在显著差异。这些发现可能有助于HCC患者的个性化临床治疗以及预测肝癌发生的风险。
The lack of information concerning individual variation in drug-metabolizing enzymes is one of the most important obstacles for designing personalized medicine approaches for hepatocellular carcinoma (HCC) patients. To assess cytochrome P450 (CYP) in the metabolism of endogenous and exogenous molecules in an HCC setting, the activity changes of 10 major CYPs in microsomes from 105 normal and 102 HCC liver tissue samples were investigated. We found that CYP activity values expressed as intrinsic clearance (CLint) differed between HCC patients and control subjects. HCC patient samples showed increased CLint for CYP2C9, CYP2D6, and CYP2E1 compared to controls. Meanwhile, CYP1A2, CYP2C8, and CYP2C19 CLint values decreased and CYP2A6, CYP2B6, and CYP3A4/5 activity was unchanged relative to controls. For patients with HCC accompanied by fibrosis or cirrhosis, the same activity changes were seen for the CYP isoforms, except for CYP2D6 which had higher values in HCC patients with cirrhosis. Moreover, CYP2D6*10 (100C>T), CYP2C9*3 (42614 A>C), and CYP3A5*3 (6986A>G) polymorphisms had definite effects on enzyme activities. In the HCC group, the CLint of CYP2D6*10 mutant homozygote was decreased by 95% compared to wild-type samples, and the frequency of this homozygote was 2.8-fold lower than the controls. In conclusion, the activities of CYP isoforms were differentially affected in HCC patients. Genetic polymorphisms of some CYP enzymes, especially CYP2D6*10, could affect enzyme activity. CYP2D6*10 allelic frequency was significantly different between HCC patients and control subjects. These findings may be useful for personalizing the clinical treatment of HCC patients as well as predicting the risk of hepatocarcinogenesis.