Host: The Japanese Society of Toxicology
[Introduction]
The liver is a major target organ of chemical toxicity, and understanding their molecular mechanisms is important for the development of new toxicity tests. Nuclear receptors (NRs) are involved in the regulation of major liver functions, and have also been known as critical targets for hepatotoxic chemicals. Here, we assessed the association between rat-derived NR-activating profiles of chemicals and their hepatotoxic phenotypes in in vivo rat toxicity studies to obtain useful information for understanding their mechanisms.
[Methods]
Using reporter assay systems in human HepG2 cells, the agonistic activity of 326 chemicals toward NRs was evaluated. Rat 28-day repeated-dose toxicity data was obtained from Hazard Evaluation Support System and the association between the in vitro activity and in vivo toxicity was investigated.
[Results and Discussion]
Reporter assays identified 36, 22, 9, 6 and 17 chemicals as positives for PXR, PPARα, LXRα, FXR and RXRα, respectively. Focusing on common in vivo phenotypes observed for the positive compounds, many of them were consistent with the typical findings associated with NR activation in rodents. For example, many positives for PXR, PPARα and RXRα were reported to induce centrilobular hepatocellular hypertrophy. In addition, several PXR positives were reported to increase serum total cholesterol and decrease blood glucose. Thus, assessing the association between the in vitro NR-activating profiles of chemicals and their in vivo rat hepatotoxic phenotypes may be useful for understanding their complex toxicological mechanism.
