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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-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.
Identifying individuals who are at increased risk of adverse drug reactions with drugs that are metabolized by UGT1A1; especially irinotecan, but also including nilotinib, pazopanib, and belinostat
Identifying individuals with Gilbert syndrome due to the presence of homozygous TA7, homozygous TA8, or compound heterozygous TA7/TA8
Identifying individuals who are carriers of Gilbert syndrome due to the presence of heterozygous TA7 or TA8
Genotyping patients who prefer not to have venipuncture done
An interpretive report will be provided.
Drug-drug interactions must be considered when predicting the UGT1A1 phenotype, especially in individuals heterozygous for the TA7 polymorphism (see Cautions). For additional information regarding pharmacogenomic genes and their associated drugs, please see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.
Samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient’s genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic blood or marrow transplantation, a pre-transplant DNA specimen is recommended for testing.
UGT1A1 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's UGT1A1 status.
Liver or renal dysfunction may result in adverse drug reactions with irinotecan independently of thymine-adenine (TA)-repeat variants.
This test does not detect or report variants other than the *28 (TA7), *36 (TA5), and *37 (TA8) alleles. Numerous variants outside of the TA repeat region have been described that impair UGT1A1 activity. Sequencing of the full gene is also available for detection of variants outside of the TA repeat region. Order UGT1 / UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Irinotecan Hypersensitivity when evaluating risk for irinotecan toxicity. Order UGT2 / UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Hyperbilirubinemia, if evaluation for Gilbert syndrome or Crigler-Najjar syndrome type I or type II is desired.
Drugs that significantly inhibit cytochrome P450 3A4, such as ketoconazole, increase patient exposure to irinotecan and its active metabolite SN-38, potentially causing or increasing the severity of an adverse drug reaction. The drug label should be consulted for additional information.
Drugs that induce the overexpression of cytochrome P450 3A4, including anticonvulsant medications (such as phenytoin, phenobarbital, and carbamazepine) and rifampin, will cause substantial reduction in exposure to irinotecan and its active metabolite SN-38. The drug label should be consulted for changes to the use of other medications.
Herbal supplements that induce the overexpression of cytochrome P450 3A4 such as St. John's Wort, will cause substantial reduction in exposure to irinotecan and its active metabolite SN-38. The drug label should be consulted for changes to the use of other medications.
An interpretive report will be provided.
1. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733
2. Gammal R, Court M, Haidar C, et al: Clinical Pharmacogenomics Implementation Consortium (CPIC) Guidelines for UGT1A1 and Atazanavir Prescribing. Clin Pharm Ther. 2015
3. Shibata T, Minami Y, Mitsuma A, et al: Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia. Int J Clin Oncol 2014;19:391-396
4. U.S. Food and Drug Administration, Pharmacogenomic Biomarkers in Drug Labeling. Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm
5. UDP-Glucuronosyltransferase Alleles Nomenclature page. Available at: http://www.pharmacogenomics.pha.ulaval.ca/cms/ugt_alleles