ReviewA comprehensive review of UDP-glucuronosyltransferase and esterases for drug development
Graphical abstract
Tissue distribution, regulation, substrate and inhibitor specificity, and species differences of UGT and esterases are summarized in this manuscript.
Introduction
Most drugs undergo metabolic biotransformation to form metabolites that are more polar than the parental compounds. Drug metabolism is divided into phase I and phase II reactions. In phase I reactions, polar groups are introduced to the molecules through oxidation, reduction, and hydrolysis. In phase II reactions, phase I metabolites or the parental compounds themselves undergo conjugation reactions with hydrophilic moieties including glucuronic acid, sulfate, glutathione, or amino acids. These reactions increase the water solubility and molecular weight of the compounds and mostly inactivate their biological activities and facilitate their efflux from the cells by transporter, followed by excretion into bile or urine. For clinically used drugs, cytochrome P450 (P450) enzymes contribute to the metabolism of two-thirds of pharmaceutical drugs, with most of the remaining drugs being metabolized by UDP-glucuronosyltransferase (UGT), esterases including carboxylesterase (CES), arylacetamide deacetylase (AADAC), butyrylcholinesterase (BCHE), and paraoxonase (PON), and flavin-containing monooxygenase (FMO) [1].
Developing a compound with desirable absorption, distribution, metabolism, and excretion (ADME) properties is essential to selecting candidate compounds in drug development. In 1991, inappropriate pharmacokinetics and bioavailability were the leading causes of attrition of a drug from the market and accounted for approximately 40% of all attrition. By 2000, these factors had been dramatically reduced to less than 10% of attrition [2], [3], probably owing to accumulated information on ADME, especially for P450 enzymes. Currently, there is a trend in drug development strategy to reduce the lipophilicity of new chemical entities, which has consequently made the non-P450 enzymes more prominent contributors to the clearance of drug candidates. Therefore, a better understanding of non-450 enzymes is required for drug development.
In this review article, we focus on UGT and esterases because these enzymes are high contributors to drug metabolism. Although information regarding these enzymes is behind that for the P450 enzymes, understanding of these enzymes is steadily increasing at a molecular and functional level. This review attempts to summarize recent progress and the present knowledge of UGTs and esterases in terms of their tissue distribution, gene regulation, substrates and inhibitors, and species differences that are useful in drug development and academic research.
Section snippets
Overview of UDP-glucuronosyltransferase
UGTs (EC 2.4.1.17) are a family of conjugating enzymes that play important roles in the metabolism of endogenous and exogenous compounds [4]. UGTs catalyze the transfer of glucuronic acid from UDP-glucuronic acid (UDPGA) to hydroxyl, carboxyl, or amine groups of hydrophobic compounds [5]. Mammalian UGTs are divided based on evolutionary divergence into two families, UGT1 and UGT2, that can be further divided into three subfamilies, UGT1A, UGT2A, and UGT2B [4]. The human UGT1A gene cluster is
Overview of esterases
Esterases catalyzing hydrolysis of esters, thioesters, and amides have been divided into three categories, A-, B-, and C-esterases. Esterases that efficiently hydrolyze organophosphates, such as paraoxon, sarin, and soman, are categorized as A-esterases [188], [189]. A representative A-esterase is PON. Esterases that are inhibited by organophosphates, carbamate, and organosulfur compounds are categorized as B-esterases. The majority of the serine esterase superfamily members containing a α/β
Conclusions
In recent drug development, the number of new chemical entities metabolized by non-CYP enzymes appears to tend to increase. Among the non-CYP enzymes, UGT and esterases highly contribute to drug metabolism. Information about UGT and esterases has been gradually accumulated, but further studies are required to increase a success rate of drug development. For UGT, although the enzyme activities had not accurately been evaluated in vitro because of their latency in microsomal membrane, improved
References (322)
Roles of glucuronidation and UDP-glucuronosyltransferases in xenobiotic bioactivation reactions
Chem Biol Interact
(2000)- et al.
Monospecfic antipeptide antibodies against human hepatic UDP-glucuronosyltransferase 1A subfamily (UGT1A) isoforms
Drug Metab Pharmacokinet
(2006) - et al.
The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification
Int J Biochem Cell Biol
(2013) - et al.
Characterization of a common deletion polymorphism of the UGT2B17 gene linked to UGT2B15
Genomics
(2004) - et al.
Differential regulation of alternate UDP-glucuronosyltransferase 1A6 gene promoters by hepatic nuclear factor-1
Toxicol Appl Pharmacol
(2003) Regulation of hepatocyte nuclear factor 4α-mediated transcription
Drug Metab Pharmacokinet
(2008)- et al.
Regulation of UDP glucuronosyltransferases in the gastrointestinal tract
Toxicol Appl Pharmacol
(2004) Function, genetic polymorphism, and transcriptional regulation of human UDP-glucuronosyltransferase (UGT) 1A1
Drug Metab Pharmacokinet
(2013)- et al.
Regulation of the human bile acid UDP-glucuronosyltransferase 1A3 by the farnesoid X receptor and bile acids
J Hepatol
(2010) - et al.
FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity
Gastroenterology
(2003)
Peroxisome proliferator-activated receptor α induces hepatic expression of the human bile acid glucuronidating UDP-glucuronosyltransferase 2B4 enzyme
J Biol Chem
The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics
Biochem Pharmacol
Genetic variability of aryl hydrocarbon receptor (AhR)-mediated regulation of the human UDP glucuronosyltransferase (UGT) 1A4 gene
Toxicol Appl Pharmacol
Aryl hydrocarbon receptor-inducible or constitutive expression of human UDP glucuronosyltransferase UGT1A6
Arch Biochem Biophys
Interaction between oxidative stress sensor Nrf2 and xenobiotic-activated aryl hydrocarbon receptor in the regulation of the human phase II detoxifying UDP-glucuronosyltransferase 1A10
J Biol Chem
UDP-Glucuronosyltransferases: gene structures of UGT1 and UGT2 families
Methods Enzymol
Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin
Arch Biochem Biophys
Regulation of CYP1A1 transcription via the metabolism of the tryptophan-derived 6-formylindolo[3,2-b]carbazole
Arch Biochem Biophys
An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements
Biochem Biophys Res Commun
Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice
J Biol Chem
CpG islands – ‘A rough guide’
FEBS Lett
Chromatin modifications and their function
Cell
Epigenetic regulation of the tissue-specific expression of human UDP-glucuronosyltransferase (UGT) 1A10
Biochem Pharmacol
N-Glycosylation plays a role in protein folding of human UGT1A9
Biochem Pharmacol
Effect of fatty acid deficiency on microsomal membrane fluidity and cooperativity of the UDP-glucuronyltransferase
Biochim Biophys Acta
Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios
Drug Metab Dispos
Can the pharmaceutical industry reduce attrition rates?
Nat Rev Drug Discov
Trial watch: phase II and phase III attrition rates 2011–2012
Nat Rev Drug Discov
Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily
Pharmacogenet Genomics
A novel method for the Immunoquantification of UDP-glucuronosyltransferases in human tissue
Drug Metab Dispos
Preparation of a specific monoclonal antibody against human UDP-glucuronosyltransferase (UGT) 1A9 and evaluation of UGT1A9 protein levels in human tissues
Drug Metab Dispos
Differential down-regulation of the UDP-glucuronosyltransferase 1A locus is an early event in human liver and biliary cancer
Cancer Res
Genetic multiplicity of the human UDP-glucuronosyltransferases and regulation in the gastrointestinal tract
Mol Pharmacol
Expression of UGT1A and UGT2B mRNA in human normal tissues and various cell lines
Drug Metab Dispos
Quantitative analysis of UDP-glucuronosyltransferase (UGT) 1A and UGT2B expression levels in human livers
Drug Metab Dispos
Determination of mRNA expression of human UDP-glucuronosyltransferases and application for localization in various human tissues by real-time reverse transcriptase-polymerase chain reaction
Drug Metab Dispos
Quantitative distribution of mRNAs encoding the 19 human UDP-glucuronosyltransferase enzymes in 26 adult and 3 fetal tissues
Xenobiotica
Quantification of human uridine-diphosphate glucuronosyl transferase 1A isoforms in liver, intestine, and kidney using nanobore liquid chromatography-tandem mass spectrometry
Anal Chem
Simultaneous absolute protein quantification of transporters, cytochromes P450, and UDP-glucuronosyltransferases as a novel approach for the characterization of individual human liver: comparison with mRNA levels and activities
Drug Metab Dispos
Absolute quantification and differential expression of drug transporters, cytochrome P450 enzymes, and UDP-glucuronosyltransferases in cultured primary human hepatocytes
Drug Metab Dispos
Targeted precise quantification of 12 human recombinant uridine-diphosphate glucuronosyl transferase 1A and 2B isoforms using nano-ultra-high-performance liquid chromatography/tandem mass spectrometry with selected reaction monitoring
Drug Metab Dispos
Targeted quantitative proteomics for the analysis of 14 UGT1As and -2Bs in human liver using NanoUPLC-MS/MS with selected reaction monitoring
J Proteome Res
Protein quantification of UDP-glucuronosyltransferases 1A1 and 2B7 in human liver microsomes by LC-MS/MS and correlation with glucuronidation activities
Xenobiotica
Optimized methods for targeted peptide-based quantification of human uridine 5′-diphosphate-glucuronosyltransferases in biological specimens using liquid chromatography–tandem mass spectrometry
Drug Metab Dispos
Simultaneous quantification of the abundance of several cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferase enzymes in human liver microsomes using multiplexed targeted proteomics
Drug Metab Dispos
Control of pancreas and liver gene expression by HNF transcription factors
Science
Activation of the mouse TATA-less and human TATA-containing UDP-glucuronosyltransferase 1A1 promoters by hepatocyte nuclear factor 1
Mol Pharmacol
Isolation of the UDP-glucuronosyltransferase 1A3 and 1A4 proximal promoters and characterization of their dependence on the transcription factor hepatocyte nuclear factor 1α
Drug Metab Dispos
Shared regulation of UGT1A7 by hepatocyte nuclear factor (HNF) 1α and HNF4α
Drug Metab Dispos
Coordinate regulation of the human UDP-glucuronosyltransferase 1A8, 1A9, and 1A10 genes by hepatocyte nuclear factor 1α and the caudal-related homeodomain protein 2
Mol Pharmacol
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These authors contributed equally to this work.