Immortalized Pig Hepatocytes: A Drug Discovery Model

DESCRIPTION (provided by applicant): Drug-drug interactions can occur in a multiple drug regimen, where one drug interferes with the metabolism of another, leading to dangerous, unpredicted, and potentially fatal concentrations of medication. Unfortunately, a significant number of such drug interactions are first recognized during clinical trials. This nonrecognition of drug metabolic interactions is due in part to interspecies differences between rodents and man. A recent FDA report estimated that up to 20 percent of toxicity and potential drug interactions are misidentified in rat assays because of interspecies differences. Most drugs are metabolized by the hepatic cytochrome P450 enzymes, and a non-primate species most reflective of human CYP regulation is the pig. MultiCell Associates recently developed an immortalized porcine hepatocyte cell line designated HepLiu. The purpose of this Phase I project is to determine if HepLiu and its MSX resistant progeny, HL-MSX, can be employed as a screening bioassay to reproducibly detect inducers and inhibitors of human CYPs. This will be accomplished by assaying 24 compounds, whose effects on CYP3A4 and 1A activity have been well documented in humans. A positive correlation will provide the scientific basis for the long term goal of this project: to develop a predictive and economical assay based on the HepLiu porcine hepatocyte cell line, for screening the CYP induction and inhibition potential of new chemical entities in drug discovery.