Uridine 5'-diphospho-glucronosyltrasferase: Its role in pharmacogenomics and human disease

Abstract

Biotransformation is an enzyme-catalyzed process in which the body converts endogenous compounds, xenobiotics and toxic substances into harmless or easily excreted metabolites. The biotransformation reactions are classified as phase I and II reactions. Uridine 5'-diphospho (UDP)-glucuronosyltransferases (UGTs) are a superfamily of phase II enzymes which have roles in the conjugation of xenobiotics or endogenous compounds, including drugs and bilirubin, with glucuronic acid to make them easier to excrete. The method the human body uses to achieve glucuronidation may be affected by a large interindividual variation due to changes in the sequences of the genes encoding these enzymes. In the last five years, the study of the genetic variants of the UGTs at a molecular level has become important due to its association with several diseases and the ability to predict adverse events due to drug metabolism. In the present review, the structure and the prominent genetic variants of the UGT1A subfamily and their metabolic and clinical implications are described.

Keywords: UGT1A1*1; UGT1A1*28; pharmacogenomics; uridine 5′-diphospho-glucuronosyltransferases.

Figure 1.

Graphical representation of the UGT1 locus. (A) The locus contains A1-A13 exons that are alternately spliced at the 5′-end of the mRNA and 2–5 common exons. Gradient-filled grey boxes correspond to pseudogenes, which do not encode for proteins. (B) UGT1A1 variants generated by the TA dinucleotide insertion/deletion in the TATA element at the A1 promoter and their effect on the enzymatic activity. (C) Alternative exon 5 (5a, 5b, or 5b plus 5a) at 3′-end of the mRNA, generating v1, v2 or v3 variants; v2 and v3 are inactive. Modified from Tourancheau et al (49). Solid black boxes correspond to genes. Black bordered boxes correspond to genes with a TA variant. Chr, chromosome; UGT, uridine 5′′-diphospho-glucuronosyltransferases.

Figure 2.

Irinotecan metabolism. Certain members of the UGT1A family are associated with the processing of SN-38. Reproduced with permission from the Pharmacogenomics Knowledge Base (PharmGKB) and Stanford University, a fully interactive version is available at: https://www.pharmgkb.org/pathway/PA2001 (81,82). CYP3A5, Cytochrome P450, family 3, subfamily A, polypeptide 5; ABCG2, ATP-binding cassette, sub-family G (WHITE), member 2; SLCO1B1, Solute carrier organic anion transporter family, member 1B1; BCHE, Butyrylcholinesterase; ABCB1, ATP-binding cassette, sub-family B (MDR/TAP), member 1; UGT1A1, UDP glucuronosyltransferase 1 family, polypeptide A1; CES2, Carboxylesterase 2; CYP3A4, Cytochrome P450, family 3, subfamily A, polypeptide 4; UGT1A10, UDP glucuronosyltransferase 1 family, polypeptide A10; UGT1A9, UDP glucuronosyltransferase 1 family, polypeptide A9; CES1, Carboxylesterase 1; ABCC2, ATP-binding cassette, sub-family C (CFTR/MRP), member 2; ABCC1, ATP-binding cassette, sub-family C (CFTR/MRP), member 1.