Host: The Japanese Society of Toxicology
The discovery of cytochrome P450 (P450) was reported in 1962 by R. Sato and T. Omura (J. Biol. Chem. 237, 1375-1376). Since then, this enzyme system has come to be recognized as having a critical role in toxicology. P450s are involved in ～ 3/4 of human enzymatic transformations of drugs and ～ 2/3 of the bioactivation of carcinogens. Bioactivation, induction, and inhibition are important aspects of P450 in toxicology, especially with drugs and drug candidates. Notable examples of P450 involvement in drug toxicity include terfenadine and acetaminophen. The toxicity of the notorious teratogen thalidomide has been revisited in the context of P450 bioactivation. Knowledge of human P450 enzymes has figured prominently in current efforts in molecular epidemiology, pharmacogenomics, chemoprevention, and risk assessment. Current issues related to P450 are predictions of drug toxicity based upon in silico modeling and the role of covalent protein binding. A general need exists to produce more innovative methods of screening for drug toxicity, with the hope of replicating the success seen in predicting metabolism and pharmacokinetics to the areas of pre-clinical toxicity and especially adverse events in humans. In summary, the understanding of P450s has been a remarkable success story in understanding the metabolism and its consequences with drugs, steroids, and carcinogens.
