Chapter 12 Cytochrome p450 (cyp) and udp-glucuronosyltransferase (ugt) enzymes: role in drug metabolism, polymorphism, and identification of their involvement in drug metabolism

Abstract

Publisher Summary The biotransformation of drugs is divided into two categories—Phase I and Phase II metabolism. Phase I reactions include oxidation, reduction, hydrolysis, and hydration. Metabolic oxidations usually occur through the action of cytochrome P450 (CYP) oxidative enzymes. Although there are at least 50 different P450 isoforms, drug metabolism in humans most likely involve CYP1A2, CYP3A4, CYP2C9, CYP2C19, and CYP2D6. P450 enzymes catalyze aromatic hydroxylation, aliphatic hydroxylation, N-, O-, and S-dealkylation; N-hydroxylation, N-oxidation, sulfoxidation, deamination,and dehalogenation. This chapter focuses on CYP enzymes for Phase I metabolism and UDP-glucuronosyltransferase (UGT) enzymes for Phase II metabolism. Understanding the involvement of P450 enzymes in drug metabolism is critical to assessing the potential for drug interaction with concomitant drugs, food, and endogenous substances. Phase I enzymes primarily modify lipophilic molecules by creating polar functionalities to increase hydrophilicity, which thereby facilitates clearance from the body. Such additional functionalities may be readily amenable to Phase II conjugation reactions. Glucuronidation is the major conjugation pathway probably due to the relatively high natural abundance of the reaction co-factor, UDP-glucuronic acid. This process occurs with alcohols, phenols, hydroxylamines, carboxylic acids, amines, sulfonamides, and thiols. The role of these enzymes in drug metabolism is reviewed within the context of their polymorphism and analytical technologies used today in determining their involvement in drug metabolism are presented.