Abstract
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.
Highlights
Drug-induced liver injury (DILI) is one of the more serious and frequent drug-related adverse events
The estimation of the potential risk of candidate compounds to induce DILI in humans is important to facilitate the development of new drugs, the estimation is difficult from the results of standard non-clinical toxicity studies
The mechanism of the fatty change is considered to be the inhibition of fatty acid β-oxidation, inhibition of respiration of the mitochondria, or inhibition of the tricarboxylic acid (TCA) cycle (Table 1)
Summary
Drug-induced liver injury (DILI) is one of the more serious and frequent drug-related adverse events. There are many drugs causing fatty change of the hepatocytes in non-clinical toxicity studies, especially in rodents and inducing DILI in humans (Table 1) These drugs include amiodarone [4], tamoxifen [5], panadiplon [6], valproic acid [7], amineptin [8], etomoxir [9], and tetracycline [10,11], all of which induce fatty change of the hepatocytes in non-clinical toxicity studies without any degenerative change in the liver. The mechanism of the fatty change is considered to be the inhibition of fatty acid β-oxidation, inhibition of respiration of the mitochondria, or inhibition of the tricarboxylic acid (TCA) cycle (Table 1) One of these drugs, valproic acid, a small branched aliphatic compound, causes fatty change of the hepatocytes in mice and rats [12,13,14]. In order to have a better understanding of the relationships between hepatic fatty change observed in non-clinical toxicity studies and DILI in humans, we investigated the mechanism for the fatty change of the hepatocytes using in vivo lipidomics analyses and in vitro mitochondrial toxicity studies for the estimation potential risk of this compound to induce DILI in humans
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
