Interindividual variation in response to xenobiotic exposure established in precision-cut human liver slices

Autores de IIS La Fe

• 

  Agustín Gerardo Lahoz Rodríguez

  Autor

• José Vicente Castell Ripoll

  Autor

Participantes ajenos a IIS La Fe

• Jetten MJ
• Claessen SM
• Dejong CH
• van Delft JH
• Kleinjans JC

Grupos

• Hepatología experimental y Trasplante hepático

• Unidad Mixta de Investigación en Hepatología Experimental

Abstract

Large differences in toxicity responses occur within the human population. In this study we evaluate whether interindividual variation in baseline enzyme activity (EA)/gene expression (GE) levels in liver predispose for the variation in toxicity responses by assessing dose-response relationships for several prototypical hepatotoxicants. Baseline levels of cytochrome-P450 (CYP) GE/EA were measured in precision-cut human liver slices. Slices (n = 4-5/compound) were exposed to a dose-range of acetaminophen, aflatoxin B1, benzo(alpha) pyrene or 2-nitrofluorene. Interindividual variation in induced genotoxicity (COMET-assay and CDKN1A/p21 GE) and cytotoxicity (lactate dehydrogenase-leakage), combined with NQO1- and GSTM1-induced GE-responses for oxidative stress and GE-responses of several CYPs was evaluated. The benchmark dose-approach was applied as a tool to model exposure responses on an individual level. Variation in baseline CYP levels, both GE and EA, can explain variation in compound exposure-responses on an individual level. Network analyses enable the definition of key parameters influencing interindividual variation after compound exposure. For 2-nitrofluorene, this analysis suggests involvement of CYP1B1 in the metabolism of this compound, which represents a novel finding. In this study, GSTM1 which is known to be highly polymorphic within the human population, but so far could not be linked to toxicity in acetaminophen-poisoned patients, is suggested to cause interindividual variability in acetaminophen-metabolism, dependent on the individual's gene expression-responses of CYP-enzymes. This study demonstrates that using interindividual variation within network modelling provides a source for the definition of essential and even new parameters involved in compound-related metabolism. This information might enable ways to make more quantitative estimates of human risks. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords

• Interindividual variation; Precision-cut liver slices; Bayesian network; Acetaminophen; Carcinogens