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

• Published in: Toxicology (Amsterdam) Vol. 323; pp. 61 - 69
• Main Authors: Jetten, Marlon J.A, Claessen, Sandra M, Dejong, Cornelis H.C, Lahoz, Agustin, Castell, José V, van Delft, Joost H.M, Kleinjans, Jos C.S
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 02-09-2014
• Subjects: Acetaminophen; Acetaminophen - toxicity; Aflatoxin B1 - toxicity; Aflatoxins; Bayesian network; Benzo(a)pyrene - toxicity; Carcinogens; Cell Survival - drug effects; Comet Assay; Cytochrome P-450 Enzyme System - genetics; DNA Damage; Emergency; Exposure; Fluorenes - toxicity; Gene Expression; Glutathione Transferase - genetics; Human; Humans; Interindividual variation; L-Lactate Dehydrogenase - metabolism; Liver; Liver - drug effects; Liver - metabolism; Mathematical models; Metabolism; NAD(P)H Dehydrogenase (Quinone) - genetics; Precision-cut liver slices; Toxicity; Xenobiotics - toxicity; APAP; benzo(a) pyrene diolepoxide; CDKN1A; Precision-cut liver slices; DMSO; NAD(P)H dehydrogenase, quinone 1; small interfering RNA; enzyme activity; 2-nitrofluorene; RT-PCR; ethylenediaminetetraacetic acid; benzo(α) pyrene; cDNA; CYP; EA; Bayesian network; 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; glutathione S-transferase mu 1; cyclin-dependent kinase inhibitor 1A; lactate dehydrogenase; sodium hydroxide; critical effect size; CES; acetaminophen; NF; GSTM1/p21; NAPQI; AFB; gene expression; Bayesian network analysis; primary human hepatocytes; NaOH; N-acetyl- p-benzoquinone imine; aryl hydrocarbon receptor; BaP; BPDE; LDH; PHH; Carcinogens; aflatoxin B1; dimethyl sulfoxide; low melting point; BMD; benchmark dose; GE; NQO1; Interindividual variation; AhR; siRNA; cytochrome P450; EDTA; LMP; copy DNA; BNA; HEPES; reverse transcription polymerase chain reaction; Acetaminophen
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2014.06.007

Highlights • Interindividual variation in GE/EA mostly exceeds variation in phenotypical endpoints. • Baseline CYP levels correlate to several response parameters over individuals. • A role for CYP1B1 in metabolism of 2-nitrofluorene is suggested by network analysis. • Network modelling is able to define key parameters in a compound-specific response.