Phase II Drug Metabolism and Individualized Drug Therapy: A Focus on Functional Genetic Variation in UDP-Glucuronosyltransferases

Yoshihiro      Maruo; Hiroko      Takahashi; Katusyuki      Matsui; Hiroshi      Sato; Yoshihiro      Takeuchi

Abstract

There have been many studies of phase-I drug metabolism (e.g., CYP450s) in personalized medicine research. By contrast, functional genetic variation in the phase-II detoxification pathways is relatively less appreciated. UDP-glucuronosyltransferases (UGTs) comprise a group of catabolic enzymes involved in the detoxification and excretion of drugs. This family glucuronidates many xenobiotic and endogenous substances in both intrahepatic and extrahepatic tissues. UGTs have two families, UGT1 and UGT2. UGT1 consists of 5 exons with a unique organization of the gene structure. There are thirteen exon 1s from UGT1A1 to UGT1A13P, whereas exon 2 to exon 5 are common to all expressed mRNAs. Each isoform of UGT1 results from differential splicing of the exon 1s to the common exon 2-5, and has a unique spectrum of substrate specificity. Nine UGT1s have been detected (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10), and are expressed in various tissues. Four exon 1s encode pseudogenes. In contrast, the gene structure of the UGT2 family consists of 6 exons, and all enzymes have an individual set of exon 1 to exon 6. There are seven UGT2B isoforms in the UGT2 family: UGT2B4, 2B7, 2B10, 2B11, 2B15, 2B17 and 2B28. UGT2A is a further subfamily of UGT2. Interestingly, UGT2A1 is expressed only in the olfactory epithelium and brain. This paper presents a critical review of the functional polymorphisms and mutations of UGTs and their impact on personalization of drug therapy. This inventory might usefully inform the next generation translational pharmacogenomics studies concerning Phase II drug metabolism.

Keywords: Drug metabolism, functional polymorphism, glucuronidation capacity, personalized medicine, phase II metabolism, UDP-glucuronosyltransferase, genetic variation, UGTs