Phenotype:UGT1A1 normal metabolizer

A UGT1A1 normal metabolizer (NM) is a person whose UGT1A1 alleles together produce the typical, reference level of enzyme activity. It is one of the three metabolizer phenotypes assigned from UGT1A1 genotype, above the poor metabolizer and intermediate metabolizer. UGT1A1 has no rapid or ultrarapid phenotype, so the normal metabolizer is the highest-activity phenotype on the scale. This page describes the normal-metabolizer phenotype; the enzyme itself is covered at Enzyme:UGT1A1.

The normal metabolizer is the reference phenotype. The standard dose of irinotecan in chemotherapy regimens is calibrated to normal-metabolizer populations, and for a normal metabolizer UGT1A1 genotype is not a reason to depart from standard dosing.

Genotype basis

The normal-metabolizer phenotype is produced by the \*1/\*1 diplotype: two copies of the reference allele, which carries the A(TA)6TAA promoter (TA6). The full allele catalogue is described on the Enzyme:UGT1A1 page.

Population frequency

The UGT1A1 normal-metabolizer phenotype is found in roughly 40 to 50% of European-ancestry populations, with frequencies elsewhere varying as the reduced-function alleles vary. Because the \*28 allele is common in every population, the normal metabolizer is typically not an overwhelming majority; in many populations the intermediate-metabolizer phenotype is as common or more so.

Clinical significance

For a UGT1A1 normal metabolizer, standard dosing of UGT1A1-affected medicines applies. Irinotecan can be given at its standard regimen dose without a genotype-driven reduction, and a normal metabolizer given atazanavir is at low risk of the clinically apparent jaundice that affects poor metabolizers.

The normal metabolizer also has a fully normal capacity to conjugate bilirubin and therefore does not have the mild unconjugated hyperbilirubinemia of Gilbert syndrome, which belongs to the poor-metabolizer phenotype.

The standing caveat applies: a normal metabolizer given a UGT1A1 inhibitor, atazanavir being the prime example, has reduced UGT1A1 function for the duration of the exposure, a phenocopy of a lower-activity phenotype. Normal-metabolizer genotype does not prevent that interaction, though the resulting hyperbilirubinemia in a normal metabolizer is milder than in a poor metabolizer.

See also

• Enzyme:UGT1A1, the enzyme, its history, and its full substrate spectrum.
• Phenotype:UGT1A1 poor metabolizer, Phenotype:UGT1A1 intermediate metabolizer, the sibling phenotypes.
• Irinotecan, Atazanavir (representative affected medicines).
• Category:Pharmacogenomic phenotypes