Using cytochrome P-450 gene knock-out mice to study chemical metabolism, toxicity, and carcinogenicity

Cytochrome P-450 (CYP) enzymes are heme-containing proteins that carry out oxidative metabolism of a wide range of structurally diverse exogenous chem icals and therapeutic agents as well as endogenous compounds. For some of t hese xenobiotics, oxidative metabolism results in the formation of toxic, m utagenic, or carcinogenic metabolites. In the past, the role of CYP enzymes in metabolism and chemical-induced toxicity was studied indirectly through use of specific antibodies or inducers and inhibitors of these enzymes. Pr ogress in molecular biology and the ability to bioengineer animal models th at do not express CYP1A2, CYP1A1, CYP1B1, CYP2E1, or both CYP1A2 and CYP2E1 isozymes has allowed for direct investigations of the in vivo role of thes e enzymes in the metabolism, toxicity, and carcinogenicity of xenobiotics. This article reviews research conducted to date that utilizes these genetic ally bioengineered mice in metabolism, toxicity, or carcinogenicity studies of chemicals. Some studies showed a positive correlation between in vivo r esults and in vitro predictions for the role of a specific CYP in chemical- induced effects, whereas other studies did not support in vitro predictions . Work reviewed herein demonstrates the importance of using animal models f or investigating the role of specific CYP enzymes in metabolism and chemica l-induced toxicity or carcinogenicity rather than relying solely on in vitr o techniques. Eventually, studies of this nature will facilitate a more acc urate assessment of human risks with regard to chemicals by helping us to u nderstand the relationships between chemical metabolism, carcinogenicity, a nd polymorphisms in CYP enzymes.