Genetic polymorphisms of the UDP-glucuronosyltransferase 1A7 gene and irinotecan toxicity in Japanese cancer patients

Irinotecan often causes unpredictably severe, occasionally fatal, toxicity involving leukopenia or diarrhea. It is converted by carboxyesterase to an active metabolite, SN-38, which is further conjugated and detoxified to SN-38-glucuronide by UDP-glucuronosyltransferase (UGT). We genotyped the UGT1A7 gene by direct sequencing analysis and polymerase chain reaction-restriction fragment length polymorphism in 118 cancer patients and 108 healthy subjects. All the patients had received irinotecan-containing chemotherapy and were evaluated to see whether the variant UGT1A7 genotype would increase the likelihood of severe toxicity of irinotecan consisting of grade 4 leukopenia and/or grade 3 or more diarrhea. Among the 26 patients with severe toxicity, the allele frequencies were 61.5% for UGTIA7*1, 15.4% for UGT1A7*2, and 23.1% for UGT1A7*3. On the other hand, the frequencies were 63.6% for UGT1A7*1, 15.8% for UGT1A7*2, and 20.7% for UGT1A7*3 among the 92 patients without severe toxicity. None of the 118 patients had UGT1A7*4. Neither univariate analysis (odds ratio, 1.13; 95% confidential interval, 0.46-2.75) nor multivariate logistic regression analysis (odds ratio, 0.74; 95% confidential interval, 0.26-2.07) found any significant association between carrying at least one of the variant alleles and the occurrence of severe toxicity. The distribution of UGT1A7 genotypes in 108 healthy subjects was not significantly different from that in the patients (P=0.99 and 0.86 for those with and without severe toxicity, respectively), but significantly less than that in Caucasians reported previously (P<0.001). The results suggested that determination of UGT1A7 genotypes would not be useful for predicting severe toxicity of irinotecan.