Chapter 22. Molecular Aspects of Drug Metabolism

Publisher Summary This chapter is intended as an overview of the molecular aspects of drug metabolism catalyzed by this hepatic enzyme system. It reviews the recent progress in the isolation and characterization of the protein components constituting this enzyme system, the interaction between these components, and the mechanism of oxygen activation. Cytochrome P450 and NADPH-cytochrome P450 reductase are the two essential protein components of the hepatic microsomal monooxygenase system. Cytochrome P450 is a b-type cytochrome with the protoporphyrin IX prosthetic group. Cytochromes of the b-type are generally characterized by low-spin heme prosthetic groups octahedrally coordinated with the two z-axial positions coordinated to the protein ligands. Although the hepatic microsomal cytochrome P450 system metabolizes compounds at a relatively low rate, it has several other features that make it uniquely suited to oxidizing the non-polar drugs. This enzyme system is able to oxidize and reduce a wide variety of structurally unrelated compounds. The oxidation of medicinal chemicals by the cytochrome P450 containing monooxygenase system is an important initial step in determining the fate of both the chemical agent and the biological system. Metabolism frequently leads to a reduction in the duration of drug action through the formation of less active metabolites and the production of compounds more readily excreted into the urine by the kidneys. This process of metabolic inactivation followed by excretion is the major pathway for terminating the action of a drug in biological systems.