Revisiting the Latency of Uridine Diphosphate-Glucuronosyltransferases (UGTs)—How Does the Endoplasmic Reticulum Membrane Influence Their Function?

Abstract

Uridine diphosphate-glucuronosyltransferases (UGTs) are phase 2 conjugation enzymes mainly located in the endoplasmic reticulum (ER) of the liver and many other tissues, and can be recovered in artificial ER membrane preparations (microsomes). They catalyze glucuronidation reactions in various aglycone substrates, contributing significantly to the body’s chemical defense mechanism. There has been controversy over the last 50 years in the UGT field with respect to the explanation for the phenomenon of latency: full UGT activity revealed by chemical or physical disruption of the microsomal membrane. Because latency can lead to inaccurate measurements of UGT activity in vitro, and subsequent underprediction of drug clearance in vivo, it is important to understand the mechanisms behind this phenomenon. Three major hypotheses have been advanced to explain UGT latency: compartmentation, conformation, and adenine nucleotide inhibition. In this review, we discuss the evidence behind each hypothesis in depth, and suggest some additional studies that may reveal more information on this intriguing phenomenon.

Comparative analysis of CYP2C8-medidated drug-drug interactions produced by CYP2C8 inhibitors, gemfibrozil versus clopidogrel, focusing on the inhibition of drug distribution in UDP-glucuronosyltransferase prior to oxidation

“…Table 4 shows the fM and fM(+) values for M6 and Des-3-OH. To calculate fM, it was assumed that the metabolites formed by CYP2C8 and CYP2C9 for Mont are restricted to M6 (fM = fm,CYP2C8 + fm,CYP2C9) [21,22], while the metabolites formed by CYP2C8 for Des are restricted to Des-3-OH (fM = fm,CYP2C8) [11]. The fM values for M6 and Des-3-OH were similar (0.56 and 0.58, respectively), while the fM(+) values for both the metabolites were decreased depending on the DDIs.…”

“…Thus, in the present study, the following model (Figure 1) was devised to predict CYP2C8mediated DDIs, referring to literature [8,[21][22][23][24][25][26][27][28][29]. The figure depicts CYP2C8-mediated oxidation using a UGT-CYP paired system, with an example of Mont.…”

“…The figure depicts CYP2C8-mediated oxidation using a UGT-CYP paired system, with an example of Mont. When Mont is oxidized by CYP2C8, a fraction of the drug (fm,(UGT-CYP)) first enters through the membrane of the endoplasmic reticulum (ER) into the lumen and is distributed to the inner space of the UGT1A, and part of the drug (fm,UGT(UGT-CY)) is metabolized to M1 (acyl glucuronide) and secreted into the ER lumen, while the remainder (fm,CYP2C8 (UGT-CYP)) is transferred to the CYP2C8 expressed on the opposite side through the ER membrane to be metabolized to M6 [8,[21][22][23][24]. Fig.…”

Homology Modeling of Human Uridine-5′-diphosphate-glucuronosyltransferase 1A6 Reveals Insights into Factors Influencing Substrate and Cosubstrate Binding

“…Uridine-5′-diphosphate glycosyltransferases (UGTs) belong to the glycosyltransferase (GT) superfamily and are responsible for the metabolism and detoxification of numerous natural compounds and xenobiotics . They make up a family of phase 2 conjugation enzymes that act to catalyze the covalent addition of sugars to lipophilic substrates and have been estimated to perform approximately 35% of all phase 2 conjugation reactions in the human body. , In humans, the UGTs are divided into four subfamilies: UGT1, 2, 3, and 8, with the most important drug-conjugating UGTs belonging to the 1 and 2 subfamilies. , The UGT1A subfamily is composed of 13 members generated from alternate splicing of a single gene on chromosome 2q37, four of which are nonfunctional pseudogenes. Exons 2–5 are common to all UGT1 members, with exon 1 and its associated promoter region unique to each member .…”

“…2,3 In humans, the UGTs are divided into four subfamilies: UGT1, 2, 3, and 8, with the most important drug-conjugating UGTs belonging to the 1 and 2 subfamilies. 4,5 The UGT1A subfamily is composed of 13 members generated from alternate splicing of a single gene on chromosome 2q37, four of which are nonfunctional pseudogenes. Exons 2−5 are common to all UGT1 members, with exon 1 and its associated promoter region unique to each member.…”