Predicting drug-induced hepatotoxicity – such as steatosis – and identifying its mechanisms can benefit from Mitologics’ technology and expertise. That is the topic of our latest research article published in April 2024 in Toxicological Sciences.
To investigate these capacities of Mitologics’ tests and know-how, 32 steatogenic and 13 nonsteatogenic drugs were tested for their ability to inhibit mitochondrial fatty acid oxidation (mtFAO) in mitochondria isolated from mouse liver.
The set of predictive toxicology tests showed a sensitivity and a positive predictive value above 88% to anticipate the occurrence of drug-induced steatosis in patients.
The combination of these predictive toxicology tests with our established MiToxView® approach can thus help to identify potential hepatotoxic drugs early at the drug discovery stage and bring a better understanding of the mechanisms of drug-induced hepatotoxicity.
A heartfelt thanks to Bernard Fromenty, PhD co-leader of the EXPRES team (NuMeCan, Inserm, University of Rennes 2) and his team, with whom Mitologics has been working since 2009.
This collaboration, part of the project MITOXDRUGS, has been supported by the ANR (Project ANR-16-CE18-0010, Programme PRCE 2016-2019).
Abstract
Drug-induced liver injury (DILI) represents a major issue for pharmaceutical companies, being a potential cause of black-box
warnings on marketed pharmaceuticals, or drug withdrawal from the market. Lipid accumulation in the liver also referred to as
steatosis, may be secondary to impaired mitochondrial fatty acid oxidation (mtFAO). However, an overall causal relationship
between drug-induced mtFAO inhibition and the occurrence of steatosis in patients has not yet been established with a high number
of pharmaceuticals. Hence, 32 steatogenic and 13 nonsteatogenic drugs were tested for their ability to inhibit mtFAO in
isolated mouse liver mitochondria. To this end, mitochondrial respiration was measured with palmitoyl-L-carnitine, palmitoyl-CoA
þ L-carnitine, or octanoyl- L-carnitine. This mtFAO tri-parametric assay was able to predict the occurrence of steatosis in patients
with a sensitivity and positive predictive value above 88%. To get further information regarding the mechanism of drug-induced
mtFAO impairment, mitochondrial respiration was also measured with malate/glutamate or succinate. Drugs such as diclofenac,
methotrexate, and troglitazone could inhibit mtFAO secondary to an impairment of the mitochondrial respiratory chain, whereas
dexamethasone, olanzapine, and zidovudine appeared to impair mtFAO directly. Mitochondrial swelling, transmembrane potential,
and production of reactive oxygen species were also assessed for all compounds. Only the steatogenic drugs amiodarone,
ketoconazole, lovastatin, and toremifene altered all these 3 mitochondrial parameters. In conclusion, our tri-parametric mtFAO
assay could be useful in predicting the occurrence of steatosis in patients. The combination of this assay with other mitochondrial
parameters could also help to better understand the mechanism of drug-induced mtFAO inhibition.
