Association between in vitro nuclear receptor-activating profiles of chemical compounds and their in vivo hepatotoxicity in rats

The liver plays critical roles to maintain homeostasis of living organisms and is also a major target organ of chemical toxicity. Meanwhile, nuclear receptors (NRs) are known to regulate major liver functions and also as a critical target for hepatotoxic compounds. In this study, we established mamm...

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Bibliographic Details
Published in:Journal of toxicological sciences 2021, Vol.46(12), pp.569-587
Main Authors: Kodama, Susumu, Yoshii, Nao, Ota, Akihiro, Takeshita, Jun-ichi, Yoshinari, Kouichi, Ono, Atsushi
Format: Article
Language:English
Subjects:
Animals
Biocompatibility
Blood coagulation
Chemical and Drug Induced Liver Injury - etiology
Chemical compounds
Clotting
Hazard assessment
Hepatomegaly
Hepatotoxicity
Homeostasis
Hybrid systems
Hypertrophy
In vitro assay
Liver
Male
Nuclear receptor
Nuclear receptors
Pregnane X Receptor
Prothrombin
Rats
Receptors
Receptors, Cytoplasmic and Nuclear
Receptors, Steroid
Repeated-dose toxicity test
Statistical analysis
Support systems
Thromboplastin
Toxicity
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Summary:The liver plays critical roles to maintain homeostasis of living organisms and is also a major target organ of chemical toxicity. Meanwhile, nuclear receptors (NRs) are known to regulate major liver functions and also as a critical target for hepatotoxic compounds. In this study, we established mammalian one-hybrid assay systems for five rat-derived NRs, namely PXR, PPARα, LXRα, FXR and RXRα, and evaluated a total of 326 compounds for their NR-activating profiles. Then, we assessed the association between their NR-activating profile and hepatotoxic endpoints in repeated-dose toxicity data of male rats from Hazard Evaluation Support System. In the in vitro cell-based assays, 68, 38, 20, 17 and 17 compounds were identified as positives for PXR, PPARα, LXRα, FXR and RXRα, respectively. The association analyses demonstrated that the PXR-positive compounds showed high frequency of endpoints related to liver hypertrophy, such as centrilobular hepatocellular hypertrophy, suggesting that PXR activation is involved in chemical-induced liver hypertrophy in rats. It is intriguing to note that the PXR-positive compounds also showed statistically significant associations with both prolonged activated partial thromboplastin time and prolonged prothrombin time, suggesting a possible involvement of PXR in the regulation of blood clotting factors. Collectively, our approach may be useful for discovering new functions of NRs as well as understanding the complex mechanism for hepatotoxicity caused by chemical compounds.
ISSN:0388-1350
1880-3989
DOI:10.2131/jts.46.569