The Functionality of UDP-Glucuronosyltransferase Genetic Variants and their Association with Drug Responses and Human Diseases.

Yazun Jarrar,Su-Jun Lee

doi:10.3390/jpm11060554

Yazun Jarrar, Su-Jun Lee

Open Access

https://doi.org/10.3390/jpm11060554

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Abstract

UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that metabolize endogenous fatty acids such as arachidonic acid metabolites, as well as many prescription drugs, such as opioids, antiepileptics, and antiviral drugs. The UGT1A and 2B genes are highly polymorphic, and their genetic variants may affect the pharmacokinetics and hence the responses of many drugs and fatty acids. This study collected data and updated the current view of the molecular functionality of genetic variants on UGT genes that impact drug responses and the susceptibility to human diseases. The functional information of UGT genetic variants with clinical associations are essential to understand the inter-individual variation in drug responses and susceptibility to toxicity.

Highlights

The UDP-glucuronosyltransferase (UGT) enzymes are phase II drug-metabolizing enzymes that catalyze the glucuronidation reaction
We showed previously that NSAIDs and the UGT2B7*2 genetic variant inhibited the glucuronidation of 20-hydroxyeicosatetraenoic acid (20-HETE) [45]
The anticonvulsant valproic acid, which causes hormonal imbalance [120], inhibited the endogenous steroidal glucuronidation by inhibiting UGT2B15, the enzyme responsible for steroid metabolism [121]. These data indicate that chemical inhibition of UGTs or loss-of-function genetic variants in the UGT genes can contribute to human disease susceptibility by increasing levels of harmful non-metabolized fatty acids in the plasma, such as 20-HETE

Summary

Introduction

The UDP-glucuronosyltransferase (UGT) enzymes are phase II drug-metabolizing enzymes that catalyze the glucuronidation reaction. This chemical reaction involves the formation of a covalent bond between the endogenous polar glucuronic acid with drugs and endogenous lipophilic compounds [1]. 2. UGT Isoforms and Genes The UGT superfamily includes many isoforms with different substrate selectivity and expression [10]. Alternative splicing of the distinct first exons with the common four exons results in the synthesis of nine different isoforms of the UGT1 family; A1 and A3–10 [11]. The isoforms of the UGT2 family contain an entirely different polypeptide sequence; their isoform genes do not share common exons, as in the UGT1 isoforms. The UGT2 family is subdivided into the UGT2A and B subfamilies [13]

Expression of UGT Isoforms

The Role of UGTs in Xenobiotic Metabolism

Factors Affecting UGT Activity

The Clinical Impact of UGT1A Genotype on Drug Response and Toxicity

The Clinical Impact of the UGT2B7 Genotype on Drug Responses and Toxicity

Conclusions