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.
Highlights
Uridine diphosphate-glucuronosyltransferases (UGTs) comprise a superfamily of phase 2 conjugation enzymes that catalyze the glucuronidation of numerous substrates at functional groups such as –OH, –COOH, –NH2, –SH, and C–C [1]
UGTs are type-I transmembrane glycoproteins mainly located within the smooth endoplasmic reticulum (ER), some isoforms can be found in the nuclear envelope [3,4]
This hypothesis is based on the assumption that the highly hydrophilic co-substrate for the glucuronidation reaction, uridine diphosphate-glucuronic acid (UDPGA), is not able to diffuse across the ER membrane, and that disruption of the membrane integrity is required to reveal the full extent of in vitro UGT activity in microsomal preparations
Summary
Uridine diphosphate-glucuronosyltransferases (UGTs) comprise a superfamily of phase 2 conjugation enzymes that catalyze the glucuronidation of numerous substrates at functional groups such as –OH, –COOH, –NH2 , –SH, and C–C [1]. They are arguably the most important conjugation enzymes facilitating the excretion of various endobiotics such as bilirubin, steroid and thyroid hormones, bile acids, and retinoids, as well as xenobiotics including environmental chemicals, pollutants, and drugs [2]. First exons, including pseudogenes, each of which is controlled by an individual promoter This mechanism of alternative splicing is conserved in human, mouse, and rat UGTs [19]
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