The HepaRG cell line: a unique in vitro tool for understanding drug metabolism and toxicology in human

被引:189
作者
Andersson, Tommy B. [1 ]
Kanebratt, Kajsa P. [2 ]
Kenna, John Gerry [3 ]
机构
[1] AstraZeneca R&D, DMPK Innovat Med, S-43183 Molndal, Sweden
[2] AstraZeneca R&D, CVGI iMed DMPK, S-43183 Molndal, Sweden
[3] AstraZeneca R&D, Global Safety Assessment, Mol Toxicol, Macclesfield, Cheshire, England
关键词
drug-metabolizing enzymes; drug transporter; HepaRG; human hepatocytes; in vitro liver models; liver toxicity; CRYOPRESERVED HUMAN HEPATOCYTES; HEPATITIS-B-VIRUS; INTERINDIVIDUAL VARIABILITY; TRANSPORTER EXPRESSION; CYP3A4; INDUCTION; CYTOCHROMES P450; TARGET GENES; MODEL; HEPATOTOXICITY; GENOTOXICITY;
D O I
10.1517/17425255.2012.685159
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Introduction: HepaRG is a unique cell line showing a great plasticity, which differentiates to both canaliculae-like and hepatocyte-like cells. The long-term stability of key cell functions, for example, the drug-metabolizing cytochrome P450 (CYP) enzyme activities, in culture is especially useful in drug metabolism, disposition and toxicity studies. Areas covered: This review describes features of the HepaRG cells focusing on drug-metabolizing enzymes and drug transporters, their functionality and regulation. Several applications in drug discovery studies are discussed and the use of HepaRG, as a human relevant predictive in vitro CYP induction model, is described. In addition, promising studies using HepaRG cells for understanding liver toxicity mechanisms by drug compounds are also discussed. Expert opinion: HepaRG cells exhibit features which make them useful as an in vitro model for drug metabolism, disposition and toxicity studies, and could, for many studies, replace the requirement for primary human hepatocytes. Care should be taken since HepaRG cells are of a specific genotype which is reflected in the expression of drug processing proteins. The finding that HepaRG cells form tight junctions provides the basis for formation of functional canalicular structures and this should be investigated further to aid development of human relevant hepatic in vitro 2D and 3D models.
引用
收藏
页码:909 / 920
页数:12
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