Molecular mechanism of phase I and phase II drug-metabolizing enzymes: implications for detoxification.
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.
Iyanagi
Takashi
T
Biometal Science Laboratory, RIKEN SPring-8 Center, Harima Institute, Hyogo 679-5148, Japan.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004579:Electron Transport; D019143:Evolution, Molecular; D014453:Glucuronosyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050216:Metabolic Detoxication, Phase I / Q000502:physiology*; D050217:Metabolic Detoxication, Phase II / Q000502:physiology*; D008659:Metabolic Diseases / Q000235:genetics / Q000503:physiopathology; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010636:Phenols / Q000378:metabolism; D011487:Protein Conformation; D013379:Substrate Specificity
D010636:Phenols; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D010100:Oxygen