UDP glucuronosyltransferase 1 family, polypeptide A1

Enzyme found in humans

UDP glucuronosyltransferase 1 1 also known as UGT 1A is an enzyme that in humans is encoded by the UGT1A1 gene. UGT 1A is a uridine diphosphate glucuronosyltransferase (UDP glucuronosyltransferase, UDPGT), an enzyme of the glucuronidation pathway that transforms small lipophilic (fat soluble) molecules, such as steroids, bilirubin, hormones, and drugs, into water soluble, excretable metabolites.

The UGT1A1 gene is part of a complex locus that encodes several UDP glucuronosyltransferases. The locus includes thirteen unique alternative first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N termini and identical C termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. Gilbert syndrome (GS) can be caused by a variety of genetic changes, but in populations of European and African descent, it is most commonly associated with the UGT1A1*28 allele (rs8175347), a homozygous 2 bp insertion (T A) mutation of the TATA box promoter region of the UGT1A1 gene. This polymorphism impairs proper transcription of UGT1A1 gene, resulting in decreased transcriptional activity of UGT1A1 by about 70%; the resulting reduced enzyme activity leads to the hyperbilirubinemia characteristic of GS. The *28 polymorphism occurs with a frequency of 26 31% in White and 42 56% of African Americans. About 10 15% of these populations are homozygous for the *28 allele, but only 5% actually develop UGT1A1 associated hyperbilirubinemia, so it appears that this mutation alone may be a necessary but not sufficient factor in GS, perhaps acting in combination with other UGT1A1 mutation(s) to increase the chances of developing GS. In these populations, Gilbert's syndrome is more often due to missense mutations in the coding region of the gene, such as UGT1A1*6 (glycine to arginine substitution at position 71 (G71R); rs4148323)
Crigler–Najjar syndrome, type II is associated with other mutation(s) that lead to a reduced activity of the mutated UGT1A1 enzyme, which causes a hyperbilirubinemia with levels of total serum bilirubin from 6 to 20 mg/dL. In this case phenobarbital treatment helps to lower bilirubin lever by more than 30%. Hyperbilirubinemia, familial transient neonatal (also called breastfeeding jaundice) is associated with mutation(s) that alone do not lead to bilirubin level increase in female patients, but their children when breastfed develop from mild to severe hyperbilirubinemia by receiving steroidal substances (with milk) inhibiting glucuronidation of unconjugated bilirubin that may lead to jaundice and even kernicterus.

Genetic variations within the UGT1A1 gene have also been associated with the development of certain drug toxicities. The UGT1A1*28 variant, the same allele behind many cases of Gilbert syndrome. The UGT1A1*28 has been associated with an increased risk for neutropenia and Diarrhea in patients receiving the chemotherapeutic drug irinotecan due to the insufficient excrete the active metabolite SN‐38, which primarily undergoes glucuronidation in livers. The U. S. Food and Drug Administration recommends on the irinotecan drug label that patients with the *28/*28 genotype receive a lower starting dose of the drug. The *28 allele has also shown associations with an increased risk for developing diarrhea in patients receiving irinotecan. The UGT1A1*6 variant, more common in Asian populations than the *28 variant, has also shown associations with the development of irinotecan toxicities. Patients who are heterozygous or homozygous for the *6 allele may have a higher risk for developing neutropenia and diarrhea as compared to those with the UGT1A1*1/*1 genotype.