Validation of in vitro methods for human cytochrome P450 enzyme induction: Outcome of a multi-laboratory study

被引：40

作者：

Bernasconi, Camilla ^{[1
]}

Pelkonen, Olavi ^{[2
,10
]}

Andersson, Tommy B. ^{[3
,4
]}

Strickland, Judy ^{[5
]}

Wilk-Zasadna, Iwona ^{[1
]}

Asturiol, David ^{[1
]}

Cole, Thomas ^{[1
]}

Liska, Roman ^{[1
]}

Worth, Andrew ^{[1
]}

Mueller-Vieira, Ursula ^{[6
,7
]}

Richert, Lysiane ^{[8
,9
]}

Chesne, Christophe ^{[9
]}

Coecke, Sandra ^{[1
]}

机构：

[1] European Commiss, Joint Res Ctr, Ispra, Italy

[2] Univ Oulu, Res Unit Biomed Pharmacol & Toxicol, Fac Med, Aapistie 5B, FIN-90014 Oulu, Finland

[3] AstraZeneca, Drug Metab & Pharmacokinet Cardiovasc Renal & Met, IMED Biotech Unit, Gothenburg, Sweden

[4] Karolinska Inst, Sect Phannacogenet, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden

[5] Integrated Lab Syst, Res Triangle Pk, NC 27709 USA

[6] Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany

[7] Boehringer Ingelheim Pharma GmbH & Co KG, Dept Drug Discovery Sci, Biberach, Germany

[8] KaLy Cell, 20A,Rue Gen Leclerc, F-67115 Plobsheim, France

[9] Biopredic Int, Parc Activite Breteche Batiment A4, F-35760 St Gregoire, France

[10] Oulu Univ Hosp, Clin Res Ctr, Oulu, Finland

来源：

TOXICOLOGY IN VITRO | 2019年 / 60卷

关键词：

CYP induction; human hepatocytes; HepaRG; metabolism; in vitro hepatic system; validation; ENDOTHELIN-RECEPTOR ANTAGONIST; CONSTITUTIVE ANDROSTANE RECEPTOR; MULTIPLE-DOSE PHARMACOKINETICS; PREGNANE X RECEPTOR; DRUG-METABOLISM; HUMAN HEPATOCYTES; ARTEMISININ ANTIMALARIALS; HEPARG CELLS; SPECIES-DIFFERENCES; NUCLEAR RECEPTORS;

D O I：

10.1016/j.tiv.2019.05.019

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 ;

摘要：

CYP enzyme induction is a sensitive biomarker for phenotypic metabolic competence of in vitro test systems; it is a key event associated with thyroid disruption, and a biomarker for toxicologically relevant nuclear receptor-mediated pathways. This paper summarises the results of a multi-laboratory validation study of two in vitro methods that assess the potential of chemicals to induce cytochrome P450 (CYP) enzyme activity, in particular CYP1A2, CYP2B6, and CYP3A4. The methods are based on the use of cryopreserved primary human hepatocytes (PHH) and human HepaRG cells. The validation study was coordinated by the European Union Reference Laboratory for Alternatives to Animal Testing of the European Commission's Joint Research Centre and involved a ring trial among six laboratories. The reproducibility was assessed within and between laboratories using a validation set of 13 selected chemicals (known human inducers and non-inducers) tested under blind conditions. The ability of the two methods to predict human CYP induction potential was assessed. Chemical space analysis confirmed that the selected chemicals are broadly representative of a diverse range of chemicals. The two methods were found to be reliable and relevant in vitro tools for the assessment of human CYP induction, with the HepaRG method being better suited for routine testing. Recommendations for the practical application of the two methods are proposed.

引用

页码：212 / 228

页数：17

共 136 条

[61] Coordinate regulation of human drug-metabolizing enzymes, and conjugate transporters by the Ah receptor, pregnane X receptor and constitutive androstane receptor [J].