UDP-glucuronosyltransferase 1-1 (UGT1A1)

UDP-glucuronosyltransferase 1A1 (UGT1A1) is a critical phase II metabolic enzyme primarily expressed in the liver that facilitates the detoxification and elimination of both endogenous and exogenous compounds. Its most vital physiological function is the conjugation of bilirubin, converting it into a water-soluble form for excretion into bile (UniProt: P22309). Beyond bilirubin, UGT1A1 is responsible for the metabolism of several therapeutic drugs, including the HIV integrase inhibitor raltegravir and the active metabolite of irinotecan, SN-38. Genetic polymorphisms, such as the UGT1A1*28 allele, can significantly reduce enzyme activity, leading to conditions like Gilbert syndrome or increased risk of severe drug toxicity (PubMed: 15173226). In clinical settings, UGT1A1 is a frequent site of drug-drug interactions; for instance, the HCV protease inhibitor faldaprevir inhibits UGT1A1 activity, which can lead to substantially increased plasma concentrations of raltegravir (PubMed: 24145534). This inhibition can also cause transient, asymptomatic increases in unconjugated bilirubin, mimicking Gilbert syndrome. Understanding the inhibitory potential of new chemical entities on UGT1A1 is essential for predicting and managing potential adverse effects and drug interactions in patients.

Other names

Bilirubin-UGT1UGT1.1GNT1HUG-BR1UDPGT 1-1UDP-glucuronosyltransferase 1A1

UGT1A1 catalyzes the transfer of a glucuronic acid moiety from UDP-glucuronic acid to various substrates, including bilirubin and drugs like raltegravir, making them more water-soluble for excretion. Faldaprevir acts as an inhibitor of UGT1A1, thereby reducing the metabolic clearance of co-administered substrates.