Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies.
Mitochondrial dysfunction is a major mechanism whereby drugs can induce liver injury and other serious side effects such as lactic acidosis and rhabdomyolysis in some patients. By severely altering mitochondrial function in the liver, drugs can induce microvesicular steatosis, a potentially severe lesion that can be associated with profound hypoglycaemia and encephalopathy. They can also trigger hepatic necrosis and/or apoptosis, causing cytolytic hepatitis, which can evolve into liver failure. Milder mitochondrial dysfunction, sometimes combined with an inhibition of triglyceride egress from the liver, can induce macrovacuolar steatosis, a benign lesion in the short term. However, in the long term this lesion can evolve in some individuals towards steatohepatitis, which itself can progress to extensive fibrosis and cirrhosis. As liver injury caused by mitochondrial dysfunction can induce the premature end of clinical trials, or drug withdrawal after marketing, it should be detected during the preclinical safety studies. Several in vitro and in vivo investigations can be performed to determine if newly developed drugs disturb mitochondrial fatty acid oxidation (FAO) and the oxidative phosphorylation (OXPHOS) process, deplete hepatic mitochondrial DNA (mtDNA), or trigger the opening of the mitochondrial permeability transition (MPT) pore. As drugs can be deleterious for hepatic mitochondria in some individuals but not in others, it may also be important to use novel animal models with underlying mitochondrial and/or metabolic abnormalities. This could help us to better predict idiosyncratic liver injury caused by drug-induced mitochondrial dysfunction.
Labbe
Gilles
G
Sanofi-aventis recherche & développement, Drug Safety Evaluation, Alfortville, France.
Pessayre
Dominique
D
Fromenty
Bernard
B
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D005234:Fatty Liver / Q000139:chemically induced / Q000503:physiopathology; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D008107:Liver Diseases / Q000473:pathology; D008930:Mitochondria, Liver / Q000187:drug effects*; D018675:Toxicity Tests