Clinical Information

Following primary metabolism by the phase I enzymes (by oxidation, reduction, dealkylation, and cleavage in the intestines and liver), many drugs and their metabolites are further modified for excretion by a group of conjugative, phase II enzymes. One of these phase II enzymes, uridine diphosphate (UDP)-glycuronosyl transferase 1A1 (UGT1A1), is responsible for phase II conjugation of certain drugs, like irinotecan. UGT1A1 is additionally responsible for glucuronide conjugation of bilirubin, which renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine. Reduced UGT1A gene transcription due to variation in the number of thymine-adenine (TA) repeats in the TATA box of the gene promoter results in reduced enzymatic activity and an increased risk for adverse outcomes in response to drugs metabolized by UGT1A1. Such TA repeat variants are also associated with Gilbert syndrome (unconjugated hyperbilirubinemia).

The TA repeat number may vary from 5 to 8 TA repeats, with 6 TA repeats being the most common allele (considered the normal allele), resulting in normal UGT1A1 expression. In addition, the rare 5 TA repeat (TA5 or *36: c.-41_-40delTA) has normal UGT1A1 expression. Individuals with 7 TA repeats (TA7 or *28: c.-41_-40dupTA) or the rare 8 TA repeats (TA8 or *37: c.-43_-40dupTATA) have decreased expression of UGT1A1. Approximately 10% to 15% of Caucasians and African Americans are homozygous for the TA7 repeat (*28/*28).

UGT1A1 is involved in the metabolism of irinotecan, a chemotherapy drug used to treat solid tumors including colon, rectal, and lung cancers. If UGT1A1 activity is reduced or deficient, the active irinotecan metabolite (SN-38) is less efficiently conjugated with glucuronic acid, which leads to an increased concentration of SN-38. This in turn can result in severe neutropenia; and the combination of neutropenia with diarrhea can be life-threatening. Individuals who are homozygous for *28 (TA7) have a 50% higher risk of experiencing severe (grade 4 or 5) neutropenia following the administration of irinotecan. Approximately 40% of individuals treated with irinotecan are heterozygous for the TA7 repeat allele (ie, TA6/TA7 or heterozygous *28). These individuals are also at increased risk of grade 4 neutropenia. The drug label for irinotecan indicates that individuals homozygous or heterozygous for TA repeat variants have a higher risk for severe or life-threatening neutropenia. The risk is thought to be greatest in individuals who receive irinotecan once every 3 weeks.

Additional drugs have also been associated with an increased risk for adverse outcomes if the patient has reduced UGT1A1 enzyme activity. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have reduced activity alleles. Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment that indicate patients who are homozygous for a reduced activity (decreased expression) allele should be considered for an alternate medication due to the significant risk for developing hyperbilirubinemia (jaundice).

Gilbert syndrome (GS), found in 5% to 10% of the population, is the most common hereditary cause of increased bilirubin and is associated with usually benign, mild hyperbilirubinemia (bilirubin levels are typically around 3 mg/dL). Gilbert syndrome is caused by a 25% to 50% reduced glucuronidation activity of the UGT1A1 enzyme and characterized by episodes of mild intermittent jaundice and the absence of liver disease. Homozygosity for the reduced activity alleles, TA7 and TA8, or compound heterozygosity (TA7/TA8) is consistent with a diagnosis of Gilbert syndrome. Heterozygosity for TA7 or TA8 is consistent with carrier status for Gilbert syndrome.