Cell based approaches for evaluation of drug-induced liver injury.
An improved understanding of mechanisms that underlie drug-induced liver injury (DILI) is required to enable design of drugs that have minimal potential to cause this adverse reaction in man. Available evidence suggests DILI arises in susceptible patients because of an imbalance between chemical insults (which are an inherent property of certain drugs and/or their metabolites) and the ability of the liver to mount compensatory/adaptive responses. In vivo safety testing in pre-clinical species ensures that drugs which enter clinical trials do not cause reproducible and dose-dependent liver injury in man, but is of limited value for exploration of underlying mechanisms and does not assess potential to cause rare idiosyncratic DILI. This review highlights the value that can be gained from in vitro studies using cultured hepatocytes and also hepatocyte-derived cell lines transfected with individual human cytochrome P450 (CYP450) isoforms. We have evaluated a range of mechanisms and endpoints (cell necrosis, mitochondrial injury, inhibition of biliary transporters and metabolite-mediated toxicity) using these model systems. Our data indicate that multiple mechanisms are likely to be involved in development of idiosyncratic DILI in man caused by numerous drugs, e.g. the anticonvulsant chlorpromazine.
Greer
Mhairi L
ML
Molecular Toxicology, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom.
Barber
Jane
J
Eakins
Julie
J
Kenna
J Gerry
JG
D000818:Animals; D001646:Bile / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000473:pathology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System