Biomimetic models for monooxygenases.

Abstract

The microsomal mixed function oxidase system contains the cytochrome P-450 oxidative drug metabolizing family of enzymes. The catalytic cycle of cytochrome P-450 is believed to involve the formation of an active iron-oxygen species which is responsible for oxygen transfer to the substrate. This assumption is supported by the fact that a number of peroxidative agents can replace NADPH, the reductase, and oxygen as co-reactants in most oxidative reactions of microsomal cytochrome P-450. We have found that a mixture of either ferrous or ferric ions with hydrogen peroxide (Fenton and Ruff reagents) can serve as biomimetic models for cytochrome P-450 in hydroxylation, exposidation, sulfoxidation, and N-demethylation of various drugs. The existance of an iron-oxo active species in both Fenton and Ruff type reactions has been postulated and provides reaction cycles similar to those of cytochrome p-450. Other model systems for the hepatic hydroxylation and epoxidation using transition metal complexes with porphyrin are also discussed. The present paper reviews the various biomimetic models of the heme cytochrome P-450 and emphasizes their simulation of hepatic drug metabolism and their potential medical and industrial applications.