Assessing cytochrome P450 function using genetically engineered mouse models

The ability to knock out and/or humanize different genes in experimental animals, globally or in cell- and tissue-specific patterns, has revolutionized scientific research in many areas. Genetically engineered mouse models, including knockout models, transgenic models, and humanized models, have played important roles in revealing the in vivo functions of various cytochrome P450 (CYP) enzymes. These functions are very diverse, ranging from the biotransformation of drugs and other xenobiotics, events that often dictate their pharmacokinetic or toxicokinetic properties and the associated therapeutic or adverse actions, to the metabolism of endogenous compounds, such as steroid hormones and other bioactive substances, that may determine susceptibility to many diseases, such as cancer and metabolic diseases. In this review, we provide a comprehensive list of Cyp-knockout, human CYP-transgenic, and CYP-humanized mouse models that target genes in the CYP1-4 gene families, and highlight their utility in assessing the in vivo metabolism, bioactivation, and toxicity of various xenobiotic compounds, including therapeutic agents and chemical carcinogens. We aim to showcase the advantages of utilizing these mouse models for in vivo drug metabolism and toxicology studies, and to encourage and facilitate greater utility of engineered mouse models to further improve our knowledge of the in vivo functions of various P450 enzymes, which is integral to our ability to develop safer and more effective therapeutics and to identify individuals predisposed to adverse drug reactions or environmental diseases.