Three dimensional aspects of metabolism in human P450 systems

Citation

Loew, G. H., Chang, Y. T., & Harris, D. (1999). Three dimensional aspects of metabolism in human P450 systems. In P. W. Erhadt (Ed.), Drug Metabolism: Databases and High-Throughput Testing During Drug Design and Development (pp. 137-144). Malden, MA: Blackwell Science.

Abstract

The ubiquitous cytochrome P450 (CYP) superfamily of metabolizing heme enzymes occur in almost all living species, including plants, bacteria, fungi, and mammalian species. More than 350 CYP isozymes have now been cloned and sequenced. The complex enzymatic cycle of this superfamily can be divided into two parts, one that is common to all of CYP enzymes and another that is isozyme dependent. The common part includes: i) the pathway to formation of the catalytically active ferryl (Fe=O) Compound I species from the inactive ferric resting form and ii) oxidation of substrates by transfer of the single active iron-bound oxygen atom from Compound I. By transfer of this single oxygen atom to a variety of substrates, the CYP enzymes have both beneficial and harmful effects. Among the beneficial effects are the solubilization and elimination of xenobiotics, processed largely by the hepatic CYP enzymes. These hepatic CYP enzymes are, however, also primarily responsible for drug toxicity, by converting benign parent therapeutic agents to toxic metabolites or by inhibition of specific CYP enzymes by these agents. The isozyme specific aspects of CYP enzyme metabolism are substrate, inhibitor, and product specificity. This specificity is the result of the large variations in the binding site architecture and amino acid composition of each CYP isozyme. It is just this specificity that determines the fate of each xenobiotic and whether or not it will lead to toxicity.