Application of toxicogenomics in hepatic systems toxicology for risk assessment: acetaminophen as a case study.
Hepatic systems toxicology is the integrative analysis of toxicogenomic technologies, e.g., transcriptomics, proteomics, and metabolomics, in combination with traditional toxicology measures to improve the understanding of mechanisms of hepatotoxic action. Hepatic toxicology studies that have employed toxicogenomic technologies to date have already provided a proof of principle for the value of hepatic systems toxicology in hazard identification. In the present review, acetaminophen is used as a model compound to discuss the application of toxicogenomics in hepatic systems toxicology for its potential role in the risk assessment process, to progress from hazard identification towards hazard characterization. The toxicogenomics-based parallelogram is used to identify current achievements and limitations of acetaminophen toxicogenomic in vivo and in vitro studies for in vitro-to-in vivo and interspecies comparisons, with the ultimate aim to extrapolate animal studies to humans in vivo. This article provides a model for comparison of more species and more in vitro models enhancing the robustness of common toxicogenomic responses and their relevance to human risk assessment. To progress to quantitative dose-response analysis needed for hazard characterization, in hepatic systems toxicology studies, generation of toxicogenomic data of multiple doses/concentrations and time points is required. Newly developed bioinformatics tools for quantitative analysis of toxicogenomic data can aid in the elucidation of dose-responsive effects. The challenge herein is to assess which toxicogenomic responses are relevant for induction of the apical effect and whether perturbations are sufficient for the induction of downstream events, eventually causing toxicity.
Laboratory for Health Protection Research, National Institute of Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands. anne.kienhuis@rivm.nl
Anne S
AS
Kienhuis
Jos G M
JG
Bessems
Jeroen L A
JL
Pennings
Marja
M
Driessen
Mirjam
M
Luijten
Joost H M
JH
van Delft
Ad A C M
AA
Peijnenburg
Leo T M
LT
van der Ven
D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D019295:Computational Biology / Q000379:methods; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018570:Risk Assessment / Q000379:methods; D018675:Toxicity Tests / Q000379:methods; D043922:Toxicogenetics / Q000379:methods*
D000082:Acetaminophen