Close association of UGT1A9 IVS1+399C>T with UGT1A1*28, *6, or *60 haplotype and its apparent influence on 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation in Japanese.
The anticancer prodrug, irinotecan, is converted to its active form 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterases, and SN-38 is inactivated by UDP-glucuronosyltransferase (UGT)1A1-mediated glucuronidation. UGT1A9 also mediates this reaction. In a recent study, it was reported that the UGT1A9 IVS1+399 (I399)C>T polymorphism is associated with increased SN-38 glucuronidation both in vitro and in vivo. However, its role in UGT1A9 expression levels and activity is controversial. Thus, we evaluated the role of I399C>T in SN-38 glucuronidation using 177 Japanese cancer patients administered irinotecan. I399C>T was detected at a 0.636 allele frequency. This polymorphism was in strong linkage disequilibrium (LD) with UGT1A9*1b (-126_-118T(9)>T(10), |D'| = 0.99) and UGT1A1*6 (211G>A, 0.86), in moderate LD with UGT1A1*60 (-3279T>G, 0.55), but weakly associated with UGT1A1*28 (-54_-39A(TA)(6)TAA>A(TA)(7)TAA, 0.25). Haplotype analysis showed that 98% of the I399C alleles were linked with low-activity haplotypes, either UGT1A1*6, *28, or *60. On the other hand, 85% of the T alleles were linked with the UGT1A1 wild-type haplotype *1. Although I399T-dependent increases in SN-38 glucuronide/SN-38 area under concentration-time curve (AUC) ratio (an in vivo marker for UGT1A activity) and decreases in SN-38 AUC/dose were apparent (P < 0.0001), these effects were no longer observed after stratified patients by UGT1A1*6, *28, or *60 haplotype. Thus, at least in Japanese populations, influence of I399C>T on SN-38 glucuronidation is attributable to its close association with either UGT1A1*6, *28, or *60.
Saito
Yoshiro
Y
Division of Functional Biochemistry and Genomics, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. yoshiro@nihs.go.jp
Sai
Kimie
K
Maekawa
Keiko
K
Kaniwa
Nahoko
N
Shirao
Kuniaki
K
Hamaguchi
Tetsuya
T
Yamamoto
Noboru
N
Kunitoh
Hideo
H
Ohe
Yuichiro
Y
Yamada
Yasuhide
Y
Tamura
Tomohide
T
Yoshida
Teruhiko
T
Minami
Hironobu
H
Ohtsu
Atsushi
A
Matsumura
Yasuhiro
Y
Saijo
Nagahiro
N
Sawada
Jun-Ichi
J
D000483:Alleles; D044466:Asian People / Q000235:genetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008040:Genetic Linkage; D020719:Glucuronides / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C441475:7-ethyl-10-hydroxycamptothecin glucuronide; C000715591:UGT1A9 protein, human