Pharmacogenomics of Human Uridine Diphospho-Glucuronosyltransferases and Clinical Implications

Abstract

Glucuronidation by uridine diphospho‐glucuronosyltransferase enzymes (UGTs) is a major phase II biotransformation pathway and, complementary to phase I metabolism and membrane transport, one of the most important cellular defense mechanisms responsible for the inactivation of therapeutic drugs, other xenobiotics, and endogenous molecules. Interindividual variability in UGT pathways is significant and may have profound pharmacological and toxicological implications. Several genetic and genomic processes underlie this variability and are discussed in relation to drug metabolism and diseases such as cancer. Clinical Pharmacology & Therapeutics (2014); 96 3, 324–339. advance online publication 16 July 2014. doi:

Quantitative Characterization of Major Hepatic UDP-Glucuronosyltransferase Enzymes in Human Liver Microsomes: Comparison of Two Proteomic Methods and Correlation with Catalytic Activity

“…Phase II drug metabolism is largely driven by the UGT family of enzymes, mainly expressed in the liver, which are responsible for approximately 35% of all conjugative metabolic pathways and are implicated in contributing to the metabolic clearance of nearly 60% of the 200 most prescribed therapeutic drugs in the United States in 2012 (Guillemette et al, 2014). The development of robust activity assays with selective UGT substrates and inhibitors has contributed to the progress of UGT-related phenotyping, where the relative contributions of different UGT enzymes to drug metabolism can be predicted, with potential applications in early characterization of drug candidates (Milne et al, 2011).…”

“…In particular, reaction phenotyping for drug-metabolizing enzymes using correlation approaches is crucially dependent on robust analytical methods used to measure both activity and expression levels in individual samples (Zientek and Youdim, 2015). However, despite recent efforts aimed at developing assays to characterize the abundance and activity of drug-metabolizing enzymes, with considerable success especially in the case of cytochrome P450 enzymes (Walsky and Obach, 2004;Gröer et al, 2014), this level of understanding is still hindered by the lack of standard and consistent methods for quantifying uridine-59-diphospho-glucuronosyltransferase (UGT) expression and function (Guillemette et al, 2014). Correlations of enzyme abundances and activity were previously demonstrated for several cytochrome P450 enzymes (Snawder and Lipscomb, 2000;Olesen and Linnet, 2001) and some UGT enzymes (mainly UGTs 1A1, 1A6, 1A9, and 2B7) (Jones et al, 2012;Sato et al, 2012;Knights et al, 2016), with a variety of substrates and different levels of correlation.…”

Quantitative profiling of the UGT transcriptome in human drug-metabolizing tissues

“…They play a critical role in regulating bioavailability of 55% of most prescribed drugs as well as important endogenous molecules including bilirubin, steroid hormones and bile acids. 4,5 In contrast, two members of the UGT3 family, UGT3A1 and UGT3A2, use respectively UDP-N-acetylglucosamine and UDP-glucose/UDP-xylose to conjugate bile acids, steroids, and bioflavones. 6 The single UGT8 family member UGT8A1 uses UDPgalactose to galactosidate ceramide as well as bile acids.…”

Multiplexed Targeted Quantitative Proteomics Predicts Hepatic Glucuronidation Potential

“…Through the expression of a complex cocktail of enzymes such as uridine 59-diphosphoglucuronosyltransferases (UGTs), the biochemical properties and bioactivity of these compounds are highly regulated by the liver. Glucuronidation contributes 35% of the phase II drug metabolic pathways and is involved in the clearance of 55% of the 200 most prescribed drugs (Guillemette et al, 2014). The liver expresses a diversified array of UGTs, with 12 of the 16 UGT1A and UGT2B proteins (Guillemette et al, 2014).…”

“…Glucuronidation contributes 35% of the phase II drug metabolic pathways and is involved in the clearance of 55% of the 200 most prescribed drugs (Guillemette et al, 2014). The liver expresses a diversified array of UGTs, with 12 of the 16 UGT1A and UGT2B proteins (Guillemette et al, 2014).The expression profile of UGTs was first described using various techniques based on mRNA and immunochemical quantification (Court et al, 2012). However, significant quantitative inaccuracy arises from the lack of correlation between mRNA and protein expression levels and the high sequence similarity among UGTs (Margaillan et al, 2015).…”