ERP016378 PRJEB14714 ena-STUDY-BAYLOR COLLEGE OF ME-06-07-2016-18:20:53:626-334 We generated a mouse model that allows conditional knock-out of the NADPH-P450 oxidoreductase (Por) gene, which is the only electron donor for all murine cytochromes and embryonic-lethal when deleted1. We introduced additional deletions in the conditional Porc/c mouse to generate a PIRF (Porc/c /Il2rg-/- /Rag2-/-/Fah-/-) strain. These data compare expression profiles in the resulting tissues. Only one out of ten drugs in development gets approved for clinical use. The majority fails during clinical trials because they are ineffective or toxic in humans; this in turn is because animal models often fail to predict human xenobiotic metabolism. Human liver chimeric mice have been a step forward in this regard, as the human hepatocytes in chimeric livers generate human metabolites. The remaining murine liver cells, however, present a challenge, since they contain an expanded set of P450 cytochromes, which form the major class of drug metabolizing enzymes. We therefore generated a mouse model that allows conditional knock-out of the NADPH-P450 oxidoreductase (Por) gene, which is the only electron donor for all murine cytochromes and embryonic-lethal when deleted1. We introduced additional deletions in the conditional Porc/c mouse to generate a PIRF (Porc/c /Il2rg-/- /Rag2-/-/Fah-/-) strain. We show that homozygous PIRF mice are fertile and their livers are readily repopulated with human hepatocytes, generating high human chimerism (>80% human). Using a two-step adenoviral strategy, we generated an almost complete deletion of the murine Por gene, leading to exclusively human cytochrome metabolism. Using the anticancer drug gefitinib, we demonstrated that Por-deleted humanized PIRF mice developed higher levels of the major human metabolite M4 and the human-specific metabolite M28 than current humanized or non-humanized mouse models. Humanized, murine Por-deficient PIRF mice can thus predict human drug metabolism and should be useful for preclinical drug development. P450oxidoreductaseDrugMetabolism Only one out of ten drugs in development gets approved for clinical use. The majority fails during clinical trials because they are ineffective or toxic in humans; this in turn is because animal models often fail to predict human xenobiotic metabolism. Human liver chimeric mice have been a step forward in this regard, as the human hepatocytes in chimeric livers generate human metabolites. The remaining murine liver cells, however, present a challenge, since they contain an expanded set of P450 cytochromes, which form the major class of drug metabolizing enzymes. We therefore generated a mouse model that allows conditional knock-out of the NADPH-P450 oxidoreductase (Por) gene, which is the only electron donor for all murine cytochromes and embryonic-lethal when deleted1. We introduced additional deletions in the conditional Porc/c mouse to generate a PIRF (Porc/c /Il2rg-/- /Rag2-/-/Fah-/-) strain. We show that homozygous PIRF mice are fertile and their livers are readily repopulated with human hepatocytes, generating high human chimerism (>80% human). Using a two-step adenoviral strategy, we generated an almost complete deletion of the murine Por gene, leading to exclusively human cytochrome metabolism. Using the anticancer drug gefitinib, we demonstrated that Por-deleted humanized PIRF mice developed higher levels of the major human metabolite M4 and the human-specific metabolite M28 than current humanized or non-humanized mouse models. Humanized, murine Por-deficient PIRF mice can thus predict human drug metabolism and should be useful for preclinical drug development. ENA-FIRST-PUBLIC 2016-07-06 ENA-LAST-UPDATE 2016-07-06