Molecular mechanism of phase I and phase II drug-metabolizing enzymes: implications for detoxification

Int Rev Cytol. 2007:260:35-112. doi: 10.1016/S0074-7696(06)60002-8.

Abstract

Enzymes that catalyze the biotransformation of drugs and xenobiotics are generally referred to as drug-metabolizing enzymes (DMEs). DMEs can be classified into two main groups: oxidative or conjugative. The NADPH-cytochrome P450 reductase (P450R)/cytochrome P450 (P450) electron transfer systems are oxidative enzymes that mediate phase I reactions, whereas the UDP-glucuronosyltransferases (UGTs) are conjugative enzymes that mediate phase II enzymes. Both enzyme systems are localized to the endoplasmic reticulum (ER) where a number of drugs are sequentially metabolized. DMEs, including P450s and UGTs, generally have a highly plastic active site that can accommodate a wide variety of substrates. The P450 and UGT genes constitute a supergene family, in which UGT proteins are encoded by distinct genes and a complex gene. Both the P450 and UGT genes have evolved to diversify their functions. This chapter reviews advances in understanding the structure and function of the P450R/P450 and UGT enzyme systems. In particular, the coordinate biotransformation of xenobiotics by phase I and II enzymes in the ER membrane is examined.

Publication types

  • Review

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme System* / chemistry
  • Cytochrome P-450 Enzyme System* / genetics
  • Cytochrome P-450 Enzyme System* / metabolism
  • Electron Transport
  • Evolution, Molecular
  • Glucuronosyltransferase* / chemistry
  • Glucuronosyltransferase* / genetics
  • Glucuronosyltransferase* / metabolism
  • Humans
  • Metabolic Detoxication, Phase I / physiology*
  • Metabolic Detoxication, Phase II / physiology*
  • Metabolic Diseases / genetics
  • Metabolic Diseases / physiopathology
  • Models, Molecular
  • Oxidation-Reduction
  • Oxygen / metabolism
  • Phenols / metabolism
  • Protein Conformation
  • Substrate Specificity

Substances

  • Phenols
  • Cytochrome P-450 Enzyme System
  • Glucuronosyltransferase
  • Oxygen