RRC ID 63927
Author Taniguchi M, Miyamoto H, Tokunaga A, Fumoto S, Tanaka T, Nishida K.
Title Evaluation of mRNA expression of drug-metabolizing enzymes in acetaminophen-induced hepatotoxicity using a three-dimensional hepatocyte culture system.
Journal Xenobiotica
Abstract 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.
Volume 50(6)
Pages 654-662
Published 2020-6-1
DOI 10.1080/00498254.2019.1683258
PMID 31631733
MeSH Acetaminophen / metabolism* Acetaminophen / toxicity Chemical and Drug Induced Liver Injury / genetics Chemical and Drug Induced Liver Injury / metabolism* Cytochrome P-450 CYP2E1 / metabolism Hep G2 Cells Hepatocytes / metabolism Humans Inactivation, Metabolic Liver Metabolic Clearance Rate RNA, Messenger / metabolism* Receptors, Cytoplasmic and Nuclear
IF 1.902
Resource
Human and Animal Cells Hep G2(RCB1886)