title: HepG2 cells as an in vitro model for evaluation of cytochrome P450 induction by xenobiotics.
abstract: Although various in vitro assays have been developed to evaluate the cytochrome P450 (CYP)-inducing potential of drug candidates, there is a continuing need for the development of a reliable model in drug discovery. The objective of the present study was to compare CYP induction by chemicals in HepG2 cells with Huh7, NKNT-3, and reverted NKNT-3 cells. HepG2 cells showed more similarity to human liver than the other cell lines in comparisons of the expression of cellular proteins. In evaluation of basal CYP activity, Huh7 cells exhibited the highest CYP1A2 and CYP3A4 activity, and HepG2 cells showed the highest CYP2B6 activity. The inducibility of CYP1A2, CYP2B6, and CYP3A4 by prototypical inducers was determined using enzyme assay, immunoblot analysis, and real-time PCR. Among the cells tested, HepG2 cells were highly responsive to CYP inducers, such as 3-methylcholanthrene for CYP1A2 and phenobarbital for CYP2B6 and CYP3A4. Moreover, HepG2 cells were responsive to various CYP1A2, CYP2B6, and CYP3A4 inducers as determined using fluorogenic and LC-MS/MS substrates. Thus, HepG2 cells may be comparable to human hepatocytes for the evaluation of CYP induction or slightly less sensitive. These results suggest HepG2 cells as a cell-based model in screening for CYP inducers in drug discovery.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, 305-764, Republic of Korea.
authors.forename: Jong Min
authors.initials: JM
authors.lastname: Choi
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Lee
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Im
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Oh
authors.forename: Chang Seon
authors.initials: CS
authors.lastname: Ryu
authors.forename: Hui Chan
authors.initials: HC
authors.lastname: Kwak
authors.forename: Ji-Yoon
authors.initials: JY
authors.lastname: Lee
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
authors.forename: Sang Kyum
authors.initials: SK
authors.lastname: Kim
mesh_terms: D002461:Cell Line, Transformed; D065693:Cytochrome P-450 Enzyme Inducers / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D065693:Cytochrome P-450 Enzyme Inducers; D015262:Xenobiotics