UGT1A1

UGT1A1, or UDP-glucuronosyltransferase 1A1, is a human gene that encodes the enzyme UDP-glucuronosyltransferase 1A1. This enzyme is part of the UGT1A family and catalyzes glucuronidation, a major phase II detoxification reaction that attaches glucuronic acid to a wide range of substrates, increasing their solubility for excretion. UGT1A1 is expressed mainly in the liver and, to a lesser extent, in the intestine and other tissues, and it participates in the metabolism of bilirubin as well as many drugs and endogenous compounds.

The UGT1A gene locus is located on chromosome 2q37 and comprises a cluster of related genes. UGT1A1 is produced from a shared locus that uses multiple first exons (alternative promoters) and splicing to generate tissue-specific isoforms, with exons 2–5 common to all. This structure allows differential regulation and activity across tissues, influencing overall glucuronidation capacity.

Genetic variation in UGT1A1 can alter enzyme activity. The most clinically relevant promoter variant is UGT1A1*28 (A(TA)7TAA), which reduces transcription and is associated with Gilbert syndrome, a common, typically mild unconjugated hyperbilirubinemia. More severe deficiency, in which UGT1A1 function is markedly reduced, underlies Crigler-Najjar syndrome types I and II.

In pharmacogenetics, UGT1A1 activity influences the metabolism of SN-38, the active metabolite of the chemotherapy drug irinotecan. Reduced UGT1A1 activity increases SN-38 exposure and risk of neutropenia and diarrhea. Variants such as *28 and *6 are linked to higher toxicity in some populations. Regulatory agencies have issued dosing guidelines and testing considerations to guide irinotecan therapy.

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