Study of P450 function using gene knockout and transgenic mice.

Abstract

The xenobiotic-metabolizing P450s have been extensively studied for their ability to metabolize endogenous and exogenous chemicals. The latter include drugs and dietary and environmentally derived toxicants and carcinogens. These enzymes also metabolize endogenous steroids and fatty acids. P450s are thought to be required for efficient removal of most xenobiotics from the body and to be responsible for the hazardous effects of toxicants and carcinogens based on their ability to convert chemicals to electrophilic metabolites that can cause cellular damage and gene mutations. P450 catalytic activities have been extensively studied in vitro and in cell culture, yielding considerable information on their mechanisms of catalysis, substrate specificities, and metabolic products. Targeted gene disruption has been used to determine the roles of P450s in intact animals and their contributions to the mechanisms of toxicity and carcinogenesis. The P450s chosen for study, CYP1A1, CYP1B1, CYP1A2, and CYP2E1, are conserved in mammals and are known to metabolize most toxicants and chemical carcinogens. Mice lacking expression of these enzymes do not differ from wild-type mice, indicating that these P450s are not required for development and physiological homeostasis. However, the P450 null mice have altered responses to the toxic and carcinogenic effects of chemicals as compared with wild-type mice. These studies establish that P450s mediate the adverse effects of drugs and dietary, environmental, and industrial chemicals and serve to validate molecular epidemiology studies that seek to determine links between P450 polymorphisms and susceptibility to chemically associated diseases. More recently, P450 humanized mice have been produced.