UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer.
OBJECTIVE
A comprehensive haplotype analysis of UGT1A1 in the Japanese population was conducted, and the effects of these haplotypes were investigated with respect to UGT1A1-related phenotypic parameters in patients with cancer who received irinotecan.


METHODS
The UGT1A1 gene, including the enhancer, the promoter, and all 5 exons and their flanking regions, was sequenced from 195 Japanese subjects. The gene was divided into 2 blocks, and the haplotypes of each block were assigned. The association of these haplotypes with area under the concentration-time curve (AUC) ratios (7-ethyl-10-hydroxycamptothecin glucuronide [SN-38G]/7-ethyl-10-hydroxycamptothecin [SN-38]) and pretreatment levels of serum total bilirubin was investigated in 85 cancer patients who received irinotecan.


RESULTS
Four haplotype groups (*1, *60, *28, and *6) were assigned in block 1, and 2 haplotype groups (*IA and *IB) were in block 2. The majority of the *IB haplotypes in block 2 were linked to either the *1 or the *60 haplotype but not to *28 in block 1. Highly significant associations were obtained between the *28 haplotypes and both a reduced AUC ratio (P =.0014, Jonckheere-Terpstra [JT] test) and an increased total bilirubin level (P =.0007, JT test). Increased total bilirubin levels in the *60 (P =.0048, JT test) and *IB groups (P =.0224, JT test) were also observed. The reduction in the AUC ratio by the *6 group was moderate (P =.0372, JT test) but was remarkable in combination with *60 (*6/*60) or *28 (*6/*28) as compared with the *1 group (*1/*1) (P =.049 and P =.0071, respectively; nonparametric Dunnett test).


CONCLUSIONS
This study identified several UGT1A1 haplotypes significantly associated with the reduced AUC ratio (*28 and *6) and with the increased total bilirubin level (*28, *60, and *IB) and suggested that the novel haplotype *IB might be functionally important. These findings will be useful for further pharmacogenetic studies on adverse reactions to irinotecan.
Sai
Kimie
K
Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan. sai@nihs.go.jp
Saeki
Mayumi
M
Saito
Yoshiro
Y
Ozawa
Shogo
S
Katori
Noriko
N
Jinno
Hideto
H
Hasegawa
Ryuichi
R
Kaniwa
Nahoko
N
Sawada
Jun-ichi
J
Komamura
Kazuo
K
Ueno
Kazuyuki
K
Kamakura
Shiro
S
Kitakaze
Masafumi
M
Kitamura
Yutaka
Y
Kamatani
Naoyuki
N
Minami
Hironobu
H
Ohtsu
Atsushi
A
Shirao
Kuniaki
K
Yoshida
Teruhiko
T
Saijo
Nagahiro
N
D000368:Aged; D001663:Bilirubin / Q000097:blood*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism*; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D020719:Glucuronides / Q000235:genetics / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D007564:Japan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000099148:UGT1A1 Enzyme
D001663:Bilirubin; D002166:Camptothecin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme