Open AccessPharmacogenetic impact of polymorphisms in the coding region of the UGT1A1 gene on SN‐38 glucuronidation in Japanese patients with cancer
Author(s) -
Araki Kazuhiro,
Fujita Kenichi,
Ando Yuichi,
Nagashima Fumio,
Yamamoto Wataru,
Endo Hisashi,
Miya Toshimichi,
Kodama Keiji,
Narabayashi Masaru,
Sasaki Yasutsuna
Publication year - 2006
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2006.00321.x
Subject(s) - irinotecan , sn 38 , pharmacogenetics , genotype , medicine , active metabolite , pharmacology , gastroenterology , metabolite , colorectal cancer , pharmacokinetics , glucuronosyltransferase , ugt2b7 , glucuronidation , biology , gene , cancer , genetics , microsome , in vitro
Pharmacogenetic testing for UDP‐glucuronosyltransferase ( UGT ) 1A1 * 28 , a promoter variant of the UGT1A1 gene, is now carried out clinically to estimate the risk of irinotecan‐associated toxicity. We studied the clinical significance of UGT1A1 * 6 and UGT1A1 * 27 , two variants in exon 1 of the UGT1A1 gene that are found mainly in Asians. The study group comprised 46 Japanese patients who received various regimens of chemotherapy including irinotecan at doses from 50 to 180 mg/m 2 . Pharmacogenetic relationships were explored between the UGT1A1 genotype and the ratio of the area under the plasma concentration–time curve (AUC) of the active metabolite of irinotecan (SN‐38) to that of SN‐38 glucuronide (SN‐38G), used as a surrogate for UGT1A1 activity (AUC SN‐38 /AUC SN‐38G ). No patient was homozygous for UGT1A1 * 28 , and none had UGT1A1 * 27 . Two were heterozygous for UGT1A1 * 28 . Two were homozygous and 15 heterozygous for UGT1A1 * 6 , all of whom were wild type with respect to UGT1A1 * 28 . Two patients were simultaneously heterozygous for UGT1A1 * 28 and UGT1A1 * 6 , present on different chromosomes. The other 25 patients had none of the variants studied. The two patients simultaneously heterozygous for UGT1A1 * 28 and UGT1A1 * 6 and the two patients homozygous for UGT1A1 * 6 had significantly higher AUC SN‐38 /AUC SN‐38G ratios than the others ( P = 0.0039). Concurrence of UGT1A1 * 28 and UGT1A1 * 6 , even when heterozygous, altered the disposition of irinotecan remarkably, potentially increasing susceptibility to toxicity. Patients homozygous for UGT1A1 * 6 should also be carefully monitored. UGT1A1 polymorphisms in the coding region of the UGT1A1 gene should be genotyped in addition to testing for UGT1A1 * 28 to more accurately predict irinotecan‐related toxicity, at least in Asian patients. ( Cancer Sci 2006; 97: 1255–1259)