The cytochrome P450 enzymes play a primary role in the metabolism of many drugs and environmental contaminants. The ability to metabolize the wide variety of substrates is accomplished, in part, by families of cytochrome P450 enzymes with relatively broad substrate specificities. As expected, the metabolism of these foreign compounds by the cytochrome P450 enzymes occurs with varying degrees of stereoselectivity. However, other interactions of these compounds and their metabolites can be very stereospecific, including the pharmacological response of drugs and some toxicities. The characterization of the stereospecific nature of cytochrome P450 mediated oxidations will provide valuable information on the pharmacokinetics of drugs and the toxicity and carcinogenicity of environmental contaminants. For example, polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants and some are believed to cause cancer in man. Carcinogen PAHs require metabolic activation by cytochrome P450 enzyme systems to exert their carcinogenic and mutagenic activities. Microsomal cytochrome P450 isozymes and epoxide hydrolase are components of the drug- metabolizing enzyme complex responsible for catalyzing regio- and stereoselective metabolism of PAHs. The resulting enantiomeric metabolites may differ in their carcinogenic activity. For example, a single enantiomer of B[a]P diolepoxide I is a potent carcinogen. While the roles of the cytochrome P450s in the stereoselective metabolism and activation of foreign compounds has been well established, the presence of multiple molecular forms of cytochrome P450s has prevented a full understanding of the role of individual forms of cytochrome P450. cDNA-directed expression of functional proteins from these cytochrome P450s via a recombinant virus expression system provides an isolated source of these enzymes.
