雄激素受体
孕烷X受体
CYP2E1
对乙酰氨基酚
药理学
CYP3A4型
细胞色素P450
肝细胞
受体
核受体
化学
酶
体外
药品
生物化学
生物
转录因子
基因
作者
Mariko Taniguchi,Hirotaka Miyamoto,Ayako Tokunaga,Shintaro Fumoto,Takashi Tanaka,Koyo Nishida
出处
期刊:Xenobiotica
[Informa]
日期:2019-11-05
卷期号:50 (6): 654-662
被引量:1
标识
DOI:10.1080/00498254.2019.1683258
摘要
1. The expression and activity of drug-metabolizing enzymes are known to affect the pharmacokinetics of drugs metabolized in the liver. Here, we assessed the effect of acetaminophen (APAP)-induced hepatotoxicity on the mRNA expression of drug-metabolizing enzymes and elucidated the underlying mechanism using three-dimensional (3D) cultures of HepG2 cells.2. 3D culture cells enabled us to establish an in vitro model of APAP-induced hepatotoxicity which showed the increase in N-acetyl-p-benzoquinone imine production, reactive oxygen species (ROS) generation and cellular injury.3. In this 3D culture model, APAP treatment significantly increased the mRNA expression of drug-metabolizing enzymes (cytochrome P450 [CYP]3A4, CYP2E1 and UDP-glucuronosyltransferase 1A6) and their nuclear receptors (pregnane X receptor and constitutive androstane receptor) compared with untreated cells. Treatment with N-acetylcysteine, a therapeutic agent for APAP-induced hepatotoxicity, suppressed these increases. In addition, the mRNA expression of drug-metabolizing enzymes and nuclear receptors were elevated depending on the concentration of H2O2, one of ROS involved in the development of APAP-induced hepatotoxicity. The mRNA expression of nuclear receptors increased before that of drug-metabolizing enzymes.4. In conclusion, ROS may induce the mRNA expression of nuclear receptors and promote the transcription of drug-metabolizing enzymes in the in vitro model of APAP-induced hepatotoxicity.
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