Parallelogram Approach Using Rat-Human In Vitro and Rat In Vivo Toxicogenomics Predicts Acetaminophen-induced Hepatotoxicity in Humans

Abstract

The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these model systems for human risk assessment by direct comparison of toxicant-induced gene expression profiles and infers mechanisms between several systems. In the present study, acetaminophen (APAP) was used as a model compound to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Comparison at the level of modulated biochemical pathways and biological processes rather than at that of individual genes appears preferable as it increases the overlap between various systems. Pathway analysis by T-profiler revealed similar biochemical pathways and biological processes repressed in rat and human hepatocytes in vitro, as well as in rat liver in vitro and in vivo. Repressed pathways comprised energy-consuming biochemical pathways, mitochondrial function, and oxidoreductase activity. The present study is the first that used a toxicogenomics-based parallelogram approach, extrapolating in vitro to in vivo and interspecies, to reveal relevant mechanisms indicative of APAP-induced liver toxicity in humans in vivo.

A risk assessment-driven quantitative comparison of gene expression profiles in PBMCs and white adipose tissue of humans and rats after isoflavone supplementation

“…Furthermore, the correlations of the isoflavone supplementation effects between these species are weak, although they are statistically significant in a number of biological pathways, including the estrogen receptor pathway, known as the predominant route of biological activity of isoflavones. Our model provided quantitative data for the effect size in two tissues of two species and the correlation between these effect sizes that could be used in existing toxicological models, such as the parallelogram approach (Kienhuis et al, 2009a;Kienhuis et al, 2009c). However, to complete and verify this parallelogram approach and to draw a conclusion regarding possible health effects of isoflavones, data on gene expression in target tissue, i.e.…”

“…Several studies have demonstrated the use of gene expression in the risk assessment of e.g. dibutyl phtalate (Euling et al, 2013a;Euling et al, 2013b;Makris et al, 2013), coumarin (Kienhuis et al, 2009a), acetaminophen (Kienhuis et al, 2009c) and benzo(a)pyrene .…”

In Vitro, In Vivo Comparison of Cyclosporin A Induced Hepatic Protein Expression Profiles

“…Accordingly, in vitro to in vivo comparisons are necessary. By applying Omics technologies it is possible to measure similar endpoints of drug-induced changes between in vitro and in vivo which enable a global comparison of both models [4].…”

“…While the conventional assays generally measure only a limited set of biological endpoints, Omics technologies offers the possibility to measure multiple endpoints simultaneously in a single experiment. Currently, transcriptomics studies, where thousands of genes are measured simultaneously, have shown to be successful for this purpose [4][5][6]. However, transcriptomics investigates the relative mRNA levels of genes which often only moderately correlate with the relative abundance of their protein product.…”

Toxicogenomic-based approaches predicting liver toxicity in vitro

“…Previous studies were rather discouraging. For example, Kienhuis et al (2009) reported that there is almost no overlap between gene expression alterations induced by paracetamol in the livers of rats compared to cultivated hepatocytes. To systematically address the possible in vitro/in vivo discrepancy, Heise and colleagues (Heise et al 2012) compared gene expression alterations induced by carcinogens in rat livers and in cultivated hepatocytes.…”