Genetic polymorphisms of UDP-glucuronosyltransferases and their functional significance
Introduction
Conjugation with glucuronic acid is responsible for the elimination of a diverse range of xenobiotics and endogenous compounds in humans and other mammalian species (Miners and Mackenzie, 1991). Glucuronidation serves as a clearance mechanism for drugs from almost all therapeutic classes as well as for numerous dietary chemicals, environmental pollutants and chemical carcinogens, and their phase I oxidation products. Endogenous compounds metabolised by glucuronidation include bile acids, bilirubin, hydroxy-steroids and thyroid hormones. Although a number of glucuronides are known to be biologically active, glucuronidation is primarily considered a detoxification process.
Glucuronidation reactions are catalysed by the microsomal enzyme, UDP-glucuronosyltransferase (UGT). Consistent with its broad substrate profile, UGT is known to exist as a superfamily of independently regulated enzymes (Mackenzie et al., 1997). UGT genes have been classified into families and subfamilies based on evolutionary divergence, with all known UGTs being included in the UGT 1A, 2A and 2B subfamilies (Mackenzie et al., 1997). Family 1 isoforms are derived from a single gene locus which spans more than 500 kb on chromosome 2q37 (Owens and Ritter, 1995, Mackenzie et al., 1997). UGT1A comprises at least 12 promoters and first exons, which are spliced separately to common exons 2–5 resulting in transcripts which encode enzymes with unique amino termini preceding an identical carboxyl terminus of 245 amino acids. The UGT1A locus encodes nine functional enzymes; UGT 1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9 and 1A10. Family 2 human enzymes include UGT 2A1, 2B4, 2B7, 2B10, 2B11, 2B15 and 2B17. UGT2 enzymes are encoded by separate genes clustered on chromosome 4 and therefore exhibit differences in amino acid sequence throughout the entire polypeptide chain.
Given the substrate profile of UGT, genetic polymorphisms of UGT isoforms are potentially of toxicological, pharmacological and physiological significance. However, while genetic polymorphism of numerous UGT isoforms has been reported, in most instances functional significance is unclear for a number of reasons; isoform substrate specificity remains poorly defined, isoforms may exhibit overlapping substrate specificity, and the domains of UGT proteins responsible for substrate binding have not been identified.
Section snippets
UGT1A1
UGT1A1 is primarily responsible for the glucuronidation of bilirubin in vivo, and hence phenotypic differences occurring as a consequence of altered expression and activity of this enzyme are more readily discernible. Three forms of inheritable unconjugated hyperbilirubinaemia exist in man; Crigler–Najjar syndromes type I and II, and Gilbert syndrome (Burchell and Hume, 1999). The former are rare genetic traits characterised by absent or very low UGT1A1 activity, and arise from mutant coding
Conclusions
Although 6 UGTs are known to exhibit genetic polymorphism, only the defects in UGT1A1 which are responsible for Gilbert syndrome have been demonstrated to be associated with altered chemical glucuronidation in humans. It is probable that polymorphic variation will occur in the coding and/or regulatory regions of all UGT isoforms, with possible altered enzyme function or expression. Unless, however, a UGT is largely responsible for the metabolism of a compound or is the predominant UGT expressed
References (20)
- et al.
cDNA cloning and expression of two new members of the human liver UDP-glucuronosyltransferase 2B subfamily
Biochem. Biophys. Res. Commun.
(1993) - et al.
Drug glucuronidation in humans
Pharmacol. Ther.
(1991) - et al.
Gene structure of the human UGT1 locus creates diversity in isozyme structure, substrate specificity and regulation
Prog. Nucleic Acid Res. Mol. Biol.
(1995) - et al.
Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis
Cancer Res.
(2000) - et al.
Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism?
Proc. Natl. Acad. Sci. USA
(1998) - et al.
Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance
Pharmacogenetics
(2000) - et al.
The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome
N. Eng. J. Med.
(1995) - et al.
Molecular genetic basis of Gilbert syndrome
J. Gastroenterol. Hepatol.
(1999) - et al.
Genetic polymorphism in the human UGT1A6 (planar phenol) UDP-glucuronosyltransferase: pharmacological implications
Pharmacogenetics
(1997) - et al.
Bilirubin UDP-glucuronosyltransferase 1A1 gene polymorphisms: susceptibility to oxidative damage and cancer?
Mol. Carcinogen
(2000)
Cited by (196)
Assessment of susceptibility to phthalate and DINCH exposure through CYP and UGT single nucleotide polymorphisms
2022, Environment InternationalCitation Excerpt :Moreover, the influence of rs1902023 on its enzyme activity has been reported inconsistently; it has been associated with with a higher clearance of total (undefined) PHs in the serum of homozygous variant allele carriers (Luo et al., 2020) and by contrast, with decreased glucuronidation capacity for some anxiolytic pharmaceuticals (e.g. oxazepam, lorazepam) in kidney cells (HK293) (Guillemette, 2003; Clarke and Jones, 2009) and bisphenol A (Hanioka et al., 2011). UGT1A7 is an extrahepatic enzyme expressed mainly in the small intestines (also in oesophagus, stomach, lungs and pancreas), and its common SNP rs11692021 (UGT1A7*3) was reported to lead to reduced activity (Guillemette et al., 2000; Miners et al., 2002; Guillemette, 2003; Clarke and Jones, 2009). However, in the present study, carriers of the rs11692021 CYP1A7*3 variant allele showed a tendency towards higher excretion of all DEHP metabolites when compared with wild-type carriers (Table SP5), but no associations were statistically significant (Table SP9).
LC-MS based metabolomic approach for the efficient identification and relative quantification of bioavailable cocoa phenolics in human urine
2021, Food ChemistryCitation Excerpt :For instance, a higher quantities of major lactone metabolites were produced by volunteers CHO-04 (female) and CHO-07 (male) compared to other volunteers (Fig. 7 and Fig. 8). Besides the quantitative variations, there could be genetic or liver enzymatic differences, which could produce different Phase-I or II metabolites (Manach et al., 2004; Miners et al., 2002). To highlight such an example in our study, CHO-10 (female) produced a smaller amount of compound (1), (2) and (3) but formed a higher amount of a non-hydroxy PVLs metabolites known as 5-(phenyl)-γVL-3′-sulfate (4) and 5-(phenyl)-γVL-3′-glucuronide (5) compared to other volunteers (Fig. 9).