108 0

Prediction of Drug-Induced Liver Injury in HepG2 Cells Cultured with Human Liver Microsomes

Title
Prediction of Drug-Induced Liver Injury in HepG2 Cells Cultured with Human Liver Microsomes
Author
김영미
Keywords
IN-VITRO METABOLISM; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; INDUCED HEPATOTOXICITY; HUMAN CYP3A4; NEFAZODONE; EXPRESSION; TOXICITY; DICLOFENAC; CYCLOPHOSPHAMIDE; BIOACTIVATION
Issue Date
2015-04
Publisher
AMER CHEMICAL SOC
Citation
CHEMICAL RESEARCH IN TOXICOLOGY, v. 28, NO 5, Page. 872-885
Abstract
Drug-induced liver injury (DILI) via metabolic activation by; drug-metabolizing enzymes, especially Cytochrome P450 (GYP), is a major,cause of drug failure and drug withdrawal., In this study; an in vitro model using HepG2 cells in combination with human liver microsomes was developed for the prediction of DILI. The cytotoxicity of cyclophosphamide, a model drug, for bioactivation was augmented in HepG2 cells cultured with microsomes in a manner dependent on exposure time, microsomal protein concentration, and NADPH Experiments using pan- or isoform-selective GYP inhibitors showed that CYP2B6 and CYP3A4 are responsible for the bioactivation of cyclophosphamide. In a metabolite identification study employing LC-ESI-QTrap and LC-ESI-QTOF, cyclophosphamide metabolites including phosphoramide mustard, a toxic metabolite, were detected in HepG2 cells cultured with microsomes, but not without microsomes The cytotoxic effects of acetaminophen and diclofenac were also potentiated by microsomes. The potentiation of acetaminophen cytotoxicity was dependent On GYP-dependent metabolism, and the augmentation of diclofenac cytotoxicity was not mediated by either CYP-,or UDP-glucuronosyltransferase-dependent metabolism. The cytotoxic effects of leflunomide, nefazodone, and bakuchiol were attenuated by microsomes. The detoxication of leflunomide by microsomes was attributed to mainly CYP3A4-dependent metabolism. The protective effect of microsomes against nefazodone Cytotoxicity was dependent on both CYP-mediated metabolism and nonspecific protein binding. Nonspecific protein binding but not GYP-dependent metabolism played a critical role, in the attenuation of bakuchiol cytotoxicity. The present study suggests that HepG2 cells cultured with human liver microsomes can be a reliable model in which to predict piu via bioactivation by drug metabolizing enzymes.
URI
http://pubs.acs.org/doi/abs/10.1021/tx500504nhttp://hdl.handle.net/20.500.11754/33858
ISSN
0893-228X; 1520-5010
DOI
10.1021/tx500504n
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE