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Evaluation of the Potential Risk of Drugs to Induce Hepatotoxicity in Human—Relationships between Hepatic Steatosis Observed in Non-Clinical Toxicity Study and Hepatotoxicity in Humans-

1
Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC., 23 Naganuki Hadano, Kanagawa 257-0024, Japan
2
Division of Medicinal Safety Science, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan
*
Author to whom correspondence should be addressed.
Academic Editors: Rolf Teschke and Gaby Danan
Int. J. Mol. Sci. 2017, 18(4), 810; https://doi.org/10.3390/ijms18040810
Received: 21 March 2017 / Revised: 6 April 2017 / Accepted: 9 April 2017 / Published: 12 April 2017
(This article belongs to the Special Issue Molecular Research on Drug Induced Liver Injury)
In the development of drugs, we sometimes encounter fatty change of the hepatocytes (steatosis) which is not accompanied by degenerative change in the liver in non-clinical toxicity studies. In this study, we investigated the relationships between fatty change of the hepatocytes noted in non-clinical toxicity studies of compound X, a candidate compound in drug development, and mitochondrial dysfunction in order to estimate the potential risk of the compound to induce drug-induced liver injury (DILI) in humans. We conducted in vivo and in vitro exploratory studies for this purpose. In vivo lipidomics analysis was conducted to investigate the relationships between alteration of the hepatic lipids and mitochondrial dysfunction. In the liver of rats treated with compound X, triglycerides containing long-chain fatty acids, which are the main energy source of the mitochondria, accumulated. Accumulation of these triglycerides was considered to be related to the inhibition of mitochondrial respiration based on the results of in vitro mitochondria toxicity studies. In conclusion, fatty change of the hepatocytes (steatosis) in non-clinical toxicity studies of drug candidates can be regarded as a critical finding for the estimation of their potential risk to induce DILI in humans when the fatty change is induced by mitochondrial dysfunction. View Full-Text
Keywords: steatosis; drug-induced liver injury; lipidomics; mitochondrial dysfunction steatosis; drug-induced liver injury; lipidomics; mitochondrial dysfunction
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Goda, K.; Kobayashi, A.; Takahashi, A.; Takahashi, T.; Saito, K.; Maekawa, K.; Saito, Y.; Sugai, S. Evaluation of the Potential Risk of Drugs to Induce Hepatotoxicity in Human—Relationships between Hepatic Steatosis Observed in Non-Clinical Toxicity Study and Hepatotoxicity in Humans-. Int. J. Mol. Sci. 2017, 18, 810.

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