3 The pharmacology of the cytochrome P450 enzyme system

The cytochrome P450 enzymes are a family of haem-oxygenases that are ubiquitously distributed throughout nature and subserve a variety of metabolic functions in man. They are the products of a gene superfamily comprising over 400 members. In man, four families (comprising about 20 major isoforms) are responsible for most of the oxidative drug metabolism which occurs primarily in the liver but which may also occur to a significant extent in other tissues. The enzymes are capable of inserting a single atom of oxygen into a vast number of structurally unrelated compounds, which explains the unique versatility of this enzyme system. This lack of substrate specificity may lead to substrate competition and thus drug interactions by enzyme inhibition. Several polymorphisms in the genes coding for P450s have been identified which may cause inter-individual variation in rates of drug metabolism, and hence therapeutic response, and in some cases, toxicity. This review describes recent advances in the pharmacology of the P450 enzymes and highlights the role of this versatile drug-oxidizing system in drug response, drug toxicity and drug interactions.