Contribution of UGT1A1 variations to chemotherapy-induced unconjugated hyperbilirubinemia in pediatric leukemia patients

BACKGROUND: Chemotherapy for malignant neoplasms sometimes induces unconjugated hyperbilirubinemia, resulting in the early cessation of treatment. We evaluated the role of variations in the bilirubin uridine-5-diphosphate (UDP)-'glucuronosyltransferase gene (UGT1A1) in unconjugated hyperbilirubinemia development during chemotherapy in pediatric patients with leukemia. METHODS: UGT1A1 allelic variations were evaluated in 25 Japanese pediatric leukemia patients with hyperbilirubinemia (peak serum bilirubin concentration 3.57 +/- 1.02 mg/dl) and 25 control patients without hyperbilirubinemia (0.92 +/- 0.32 mg/dl) by PCR-direct sequencing. RESULTS: In the hyperbilirubinemic group, 22 of 25 patients showed biallelic variations of UGT1A1. Nine (36%) patients were homozygous for UGT1A1*6 and eight (32%) were compound heterozygous for UGT1A1*6 and UGT1A1*28. Three (12%) patients were homozygous for UGT1A1*28. There were no biallelic variations in UGT1A1 in the non-hyperbilirubinemic group. The allelic frequencies of UGT1A1*6 in the hyperbilirubinemic group (0.58) was significantly higher than those of the non-hyperbilirubinemic group (0.1) (chi(2) = 25.7, P < 0.05). CONCLUSION: The high frequency of biallelic variations of UGT1A1 in the hyperbilirubinemic group suggests an association with Gilbert syndrome. Therefore, it is not necessary to cease chemotherapy in patients with these mutations who develop unconjugated hyperbilirubinemia without associated liver dysfunction.