Cytochrome P450: Enzyme regulation and toxicological significance

Abstract

The pharmacological and toxicological responses of drugs and environmental chemicals are dependent upon metabolism of the compounds. Cytochrome P450 (P450)-dependent monooxygenases are the primary enzyme system responsible for the oxidative metabolism of drugs, carcinogens, food additives, and environmental chemicals. The underlying basis for the broad substrate specificity of P450 is that there are multiple forms of P450. A nomenclature system based on amino acid sequence homology is adopted for the increasing number of P450 hemoproteins. P450 genes are subject to regulation by many physiological and environmental factors. Regulation of P450 enzymes shows marked species and tissue specificity which plays an important role in species and tissue extrapolation of chemical risk assessment and target organ toxicity. P450 isoforms are readily inducible following exposure to foreign compounds of which phenobarbital, 3-methylcholanthrene, and ethanol are the prototypic inducing agents. Many drugs and natural compounds are potent inhibitors of P450 and dependent catalytic activity. Mechanism of P450 regulation also shows multiplicity at the transcriptional, translational, and post-translational stages. Polymorphism and racial difference are important determinants of drug metabolism and susceptibility to diseases in humans. Traditional Chinese medicines have the ability to induce and inhibit multiple forms of P450 monooxygenases. Expression of human P450 in mammalian cell lines provides an alternative system to study the functions of P450s in xenobiotic metabolism and toxicity in humans. P450 may be assoicated with regulation of cellular entry of calcium. Finally, the perspective of future P450 research is discussed.