Effect of methamphetamine on clock genes and drug-metabolizing enzyme expression
Effect of methamphetamine on clock genes and drug-metabolizing enzyme expression
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DOI：
10.1177/09603271221124092
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发表时间：
2022-01
影响因子：
2.8
通讯作者：
Naoto Tani;Tomoya Ikeda;T. Ishikawa
中科院分区：
文献类型：
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作者：
Naoto Tani;Tomoya Ikeda;T. Ishikawa
本研究从药物代谢的角度探讨时钟基因表达与甲基苯丙胺（MA）对药物代谢酶的影响之间的关系。利用ma中毒死亡尸检病例的肝脏研究时钟基因BMAL1和PER2的表达与药物代谢酶CYP3A4和CYP2D6的关系。此外，我们还检测了MA暴露对HepG2人肝癌细胞中各种基因的影响。根据血MA浓度比较MA使用者各基因的表达，CYP3A4表达与PER2相似，CYP2D6表达与BMAL1相似。在培养细胞实验中，添加MA后，BMAL1和CYP2D6的表达随时间的延长而降低，PER2和CYP3A4的表达随浓度的增加而略有增加。这些结果与尸检结果一致。在BMAL1和PER2抑制下，CYP3A4和CYP2D6的表达上调，而在PER2单独抑制下，CYP2D6的表达上调。这些结果表明CYPs在MA代谢过程中受时钟基因BMAL1和PER2的调控。
This study examined the association between clock gene expression and the effect of methamphetamine (MA) on drug-metabolizing enzymes from the perspective of drug metabolism. The relationship between expression of the clock genes BMAL1 and PER2 and the drug-metabolizing enzymes CYP3A4 and CYP2D6 was investigated using livers from autopsy cases of MA-intoxication deaths. Additionally, the effect of MA exposure on various genes was examined in HepG2 human hepatocellular carcinoma cells. Comparisons of the expression of various genes in MA users according to blood MA concentration revealed that CYP3A4 expression was similar to that of PER2, and CYP2D6 expression was similar to that of BMAL1. In cultured cell experiments, BMAL1 and CYP2D6 expression decreased depending on the time elapsed after MA addition, and PER2 and CYP3A4 expression increased slightly in a concentration-dependent manner. These results were consistent with the findings of autopsy examinations. Expression of CYP3A4 and CYP2D6 under BMAL1 and PER2 suppression, but not CYP2D6 under PER2 suppression alone, was upregulated in response to MA. These results suggest that CYPs are regulated via the clock genes BMAL1 and PER2 during MA metabolism.