The Proliferating P450s: Providers of Polysubstrate Pharmacology

Summary

Over 300 P450s have been cloned and sequenced. A gene superfamily composed of at least 36 gene families has been described in 31 eukaryotes (including 11 mammalian and three plant species). Twelve families, made up of 22 subfamilies, exist in all mammals examined to date including 36 P450s identified in humans. Substrates for P450s represent a wide range of endogeneous and xenobiotic chemicals — including a large number of pharmacologically active drugs. Current areas of research on P450 focus on differences in protein structure related to the specificity of substrate structure for metabolism, the identify and response of specific transcriptional regulatory elements influencing the induction of individual P450s, the frequency of polymorphisms and their impact on drug metabolism and susceptibility to cancer, and the heterologous expression of functional P450s in systems that, can be applied to drug discovery and toxicity evaluation studies. The diversity of P450s and their versatility in the metabolism of drugs continues to challenge the pharmacologist.