A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development

Abstract

UDP-glucuronosyltransferase (UGT) and esterases are recognized as the most important non-P450 enzymes because of their high contribution to drug metabolism. UGTs catalyze the transfer of glucuronic acid to hydroxyl, carboxyl, or amine groups of compounds, whereas esterases hydrolyze compounds that contain ester, amide, and thioester bonds. These enzymes, in most cases, convert hydrophobic compounds to water-soluble metabolites to facilitate the elimination of compounds from the body. Information about these enzymes is steadily increasing, although our knowledge is still behind our understanding of P450. This review gives an overview of recent findings in UGT and esterases studies focusing on tissue distribution, gene regulation, substrate and inhibitor specificity, and species differences. In particular, the absolute protein content of UGT isoforms and esterases in human tissues could be available. In the field of esterases, it is becoming clear that enzymes other than carboxylesterase are involved in drug hydrolysis. In addition, there is an interesting interplay between UGTs and esterases in the formation and hydrolytic deglucuronidation of acyl-glucuronide, which is considered to be a reactive metabolite. With the growing awareness of the importance of non-P450 enzymes in drug development, issues that should be resolved are discussed.

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.