Chemical Probes for Human UDP‐Glucuronosyltransferases: A Comprehensive Review

Abstract

UGTs play crucial roles in the metabolism and detoxification of both endogenous and xenobiotic compounds. The key roles of UGTs in human health have garnered great interest in the design and development of specific probes for human UGTs. However, in contrast to other human enzymes, the probe substrates for human UGTs are rarely reported, owing to the highly overlapping substrate specificities of UGTs and the lack of the integrated crystal structures of UGTs. Over the past decades, many efforts are made to develop specific probe substrates for UGTs and use them in both basic research and drug discovery. This review focuses on recent progress in the development of probe substrates for UGTs and their biomedical applications. A long list of chemical probes for UGTs, including non-fluorescent and fluorescent probes along with their structural information and kinetic parameters, are prepared and analyzed. Additionally, challenges and future directions in this field are highlighted in the final section. All information and knowledge presented in this review provide practical tools/methods for measuring UGT activities in complex biological samples, which will be very helpful for rapid screening and characterization of UGT modulators, and for exploring the relevance of UGT enzymes to human diseases.

Identification of equol‐7‐glucuronide‐4′‐sulfate, monoglucuronides and monosulfates in human plasma of 2 equol producers after administration of kinako by LC‐ESI‐MS

“…The SULTs responsible for the sulfonation of Dein and Gein are mainly SULT 1A1 for monosulfation at the 4′‐ or 7 ‐position and SULT 1E1 for disulfation at both positions . Expression and function of these enzymes may be influenced by factors such as age, race, genetic polymorphisms, and gender . Although the reason for the different occurrence of E‐7G‐4′S and E‐7S‐4′G as metabolites in human plasma is unclear, the data collected in this study on the plasma profile of equol producers will furnish useful information on the metabolism and disposition of phase II metabolites.…”

Inhibition of UGT1A1 by natural and synthetic flavonoids

“…In the present study, more than fifty flavonoids were collected and their inhibitory effects on the human UGT1A1 were investigated carefully. A florescence-based biochemical assay was constructed for high-throughput screening of UGT1A1 inhibitors, in which the newly developed fluorescent substrate for UGT1A1 was used as a probe [47,[49][50] and human liver microsomes (HLM) as the enzyme source. The potential structure-inhibition relationships of these structurally diverse flavonoids have been summarized and discussed.…”

An investigation of the metabolic activity, isozyme contribution, species differences and potential drug–drug interactions of PI-103, and the identification of efflux transporters for PI-103-O-glucuronide in HeLa1A9 cells

“…Additionally, human CYPs and UGTs are primarily responsible for the elimination and detoxication of xenobiotics (e.g., clinical drugs, carcinogens, pollutants) and maintaining the balance of endogenous substances (e.g., bilirubin, estrogens, bile acids). [10][11][12] Inhibition of human CYP or UGT functions can not only trigger potentially adverse clinical DDIs, but could also result in metabolic disorders for endogenous molecules. [13][14][15] Considering the potential co-administration of PI-103 with other chemotherapeutic drugs, it is crucial to evaluate the potential risks of DDI in clinics.…”