Cytochrome p450: What have we learned and what are the future issues?

The cytochrome P450 (P450) field came out of interest in the metabolism of drugs, carcinogens, and steroids, which remain major focal points. Over the years we have come to understand the P450 system components, the multiplicity of P450s, and many aspects of the regulation of the genes and also the catalytic mechanism. Many crystal structures are now becoming available. The significance of P450 in in vivo metabolism is appreciated, particularly in the context of pharmacogenetics. Current scientific issues involve posttranslational modification, gene regulation, component interactions, structures of P450 complexed with ligands, details of high-valent oxygen chemistry, the nature and influence of rate-limiting steps, greater details about some reaction steps, cooperativity, and the relevance of P450 variations to cancer risk. Some emerging research areas involve new methods of analysis of ligand interactions, roles of conformational changes linked to individual reaction steps, functions of orphan P450s, "molecular breeding" of new P450 functions and enhanced activity, and the utilization of P450s in chemical synthesis.