The clinical application of UGT1A1 pharmacogenetic testing: Gene-environment interactions

The uridine diphosphate glucuronosyltransferase (UGT) enzymes are a superfamily of conjugating enzymes that aid in the excretion of several molecules by transferring one glucuronic acid to their substrates. This makes them more hydrophilic molecules and enables their biliary or renal elimination [1]. This superfamily consists of two families (UGT1, UGT2) and three subfamilies (UGT1A, UGT2A, UGT2B). The UGT2 family comprises eight different proteins encoded by individual genes located on chromosome 4q13, while the first subfamily (UGT1A) comprises nine proteins and is coded by the UGT1A gene, located on chromosome 2q37. This locus contains each isoform's unique exon 1 and the common exons 2-5, present in all transcripts [2]. Some UGT isoforms are tissue specific [3]. There is evidence of substrate overlap, although some substrates are specific for one particular isoform, such as the conjugation of bilirubin, which is mainly catalysed by UGT1A1 [1-3].UGT1A1 is the focus of this report.To date, more than 150 functional polymorphisms have been identified on the UGT1A locus, and 113 functional variants have been identified specifically in UGT1A1 [1,4]. These allelic variations were found in both the exonic and promoter sequences. The most thoroughly studied of these polymorphisms is UGT1A1*28, representing seven thymine-adenine (TA) repeats in the promoter region of UGT1A1. Individuals with this variant have an extra TA repeat in this sequence, whereas the wild-type allele comprises six repeats and is denoted as UGT1A1*1 [1,2,5]. The length of this TA repeat sequence is inversely correlated with the activity of the UGT1A1 enzyme; therefore, the *28 polymorphism results in reduced UGT1A1 activity, which affects the elimination of its drug substrates. When the *28 allele is present on only one chromosome, it results in a 25 per cent decrease in enzyme activity[6] and, when present in a homozygous fashion, UGT1A1 transcription is reduced by 70 per cent [1,2,4,5]. In additio