A novel humanized mouse lacking murine P450 oxidoreductase for studying human drug metabolism.

ABSTRACT: Only one out of 10 drugs in development passes clinical trials. Many fail because experimental animal models poorly predict human xenobiotic metabolism. Human liver chimeric mice are a step forward in this regard, as the human hepatocytes in chimeric livers generate human metabolites, but the remaining murine hepatocytes contain an expanded set of P450 cytochromes that form the major class of drug-metabolizing enzymes. We therefore generated a conditional knock-out of the NADPH-P450 oxidoreductase (Por) gene combined with Il2rg ^{- /-} /Rag2 ^{- /-} /Fah ^{- /-} (PIRF) mice. Here we show that homozygous PIRF mouse livers are readily repopulated with human hepatocytes, and when the murine Por gene is deleted (<5%), they predominantly use human cytochrome metabolism.

SUBMITTER: Barzi M 

PROVIDER: S-EPMC5489481 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature