Phenotype:UGT1A1 poor metabolizer

A UGT1A1 poor metabolizer (PM) is a person who carries two reduced-function UGT1A1 alleles and therefore has substantially reduced UGT1A1 enzyme activity. It is one of the three metabolizer phenotypes assigned from UGT1A1 genotype, the others being the intermediate metabolizer and the normal metabolizer. UGT1A1 has no ultrarapid phenotype. This page describes the poor-metabolizer phenotype; the enzyme itself, including its history and the Gilbert syndrome story, is covered at Enzyme:UGT1A1.

The UGT1A1 poor-metabolizer phenotype has a feature no other phenotype page in this category shares: it is, biochemically, a named clinical condition in its own right. The reduced UGT1A1 activity of the poor metabolizer is the molecular basis of Gilbert syndrome, the common, benign, inherited mild unconjugated hyperbilirubinemia. A UGT1A1 poor metabolizer and a person with Gilbert syndrome are, in genotype terms, the same person.

Genotype basis

The poor-metabolizer phenotype is produced by a UGT1A1 diplotype combining two reduced-function alleles. The clinically important alleles:

• \*28 (the A(TA)7TAA promoter variant, TA7), the classic Gilbert syndrome allele, common in all populations and most frequent in African-ancestry populations.
• \*6 (Gly71Arg), a reduced-function allele common in East Asian populations and uncommon elsewhere.
• \*37 (the A(TA)8TAA promoter variant, TA8), a more severely reduced-function allele found in some African-ancestry populations.

Diplotypes such as \*28/\*28, \*6/\*6, and \*37/\*37 produce the poor-metabolizer phenotype. The \*28/\*28 genotype is the one most often quoted in the irinotecan literature. The full allele catalogue is described on the Enzyme:UGT1A1 page.

Population frequency

The UGT1A1 poor-metabolizer phenotype is found in roughly 10% of European-ancestry populations, 5 to 10% of African-ancestry populations, and 1 to 5% of East Asian populations. The figure for Gilbert syndrome quoted in general medicine, often around 5 to 10% of the population, is the same phenomenon counted the same way.

Clinical consequences

Irinotecan (clearance; raised exposure of the toxic metabolite). The cytotoxic medicine irinotecan is converted in the body to its active metabolite SN-38, and UGT1A1 is the enzyme that glucuronidates SN-38 to an inactive form for excretion. A UGT1A1 poor metabolizer clears SN-38 slowly, accumulates it, and is at markedly elevated risk of severe neutropenia and severe diarrhea. The Dutch Pharmacogenetics Working Group recommends a starting-dose reduction of about 30% for \*28/\*28 patients receiving irinotecan in standard regimens, with the option to titrate upward if severe neutropenia does not occur.

Atazanavir (hyperbilirubinemia). The HIV protease inhibitor atazanavir inhibits UGT1A1. Given to a UGT1A1 poor metabolizer, whose UGT1A1 activity is already low, atazanavir reliably produces clinically apparent unconjugated hyperbilirubinemia and visible jaundice. The jaundice is biochemically benign but is cosmetically distressing and a frequent reason for patient-initiated discontinuation; CPIC recommends considering an alternative protease inhibitor in poor metabolizers for whom the jaundice would be unacceptable.

Bilirubin and Gilbert syndrome. The poor metabolizer has a reduced capacity to conjugate bilirubin and therefore a mildly raised unconjugated bilirubin, most visible during fasting, intercurrent illness, or physical stress. This is Gilbert syndrome, and on its own it is benign and requires no treatment; its main clinical importance is that it must not be mistaken for a sign of liver disease or hemolysis.

See also

• Enzyme:UGT1A1, the enzyme, its history, and its full substrate spectrum.
• Phenotype:UGT1A1 intermediate metabolizer, Phenotype:UGT1A1 normal metabolizer, the sibling phenotypes.
• Irinotecan, Atazanavir (representative affected medicines); Gilbert syndrome, Bilirubin (the endogenous context).
• Category:Pharmacogenomic phenotypes