title: Interindividual variation in response to xenobiotic exposure established in precision-cut human liver slices.
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(α) 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.
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands. Electronic address: marlon.jetten@maastrichtuniversity.nl.
authors.forename: Marlon J A
authors.initials: MJ
authors.lastname: Jetten
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Claessen
authors.affiliation: Department of Surgery, Maastricht University, Maastricht, The Netherlands.
authors.forename: Cornelis H C
authors.initials: CH
authors.lastname: Dejong
authors.affiliation: Unidad de Hepatología Experimental, CIBERehd, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
authors.forename: Agustin
authors.initials: A
authors.lastname: Lahoz
authors.affiliation: Unidad de Hepatología Experimental, CIBERehd, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
authors.forename: José V
authors.initials: JV
authors.lastname: Castell
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands.
authors.forename: Joost H M
authors.initials: JH
authors.lastname: van Delft
authors.affiliation: Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands.
authors.forename: Jos C S
authors.initials: JC
authors.lastname: Kleinjans
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D016604:Aflatoxin B1 / Q000633:toxicity; D001564:Benzo(a)pyrene / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004249:DNA Damage; D005449:Fluorenes / Q000633:toxicity; D015870:Gene Expression; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D015262:Xenobiotics / Q000633:toxicity*
chemical_list: D000082:Acetaminophen; D016604:Aflatoxin B1; D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System; D005449:Fluorenes; D005982:Glutathione Transferase; D007770:L-Lactate Dehydrogenase; D016660:NAD(P)H Dehydrogenase (Quinone); D015262:Xenobiotics; C019499:2-nitrofluorene; C447479:NQO1 protein, human
keywords: Acetaminophen; Bayesian network; Carcinogens; Interindividual variation; Precision-cut liver slices