UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer

• Published in: Clinical pharmacology and therapeutics Vol. 75; no. 6; p. 501
• Main Authors: Sai, Kimie, Saeki, Mayumi, Saito, Yoshiro, Ozawa, Shogo, Katori, Noriko, Jinno, Hideto, Hasegawa, Ryuichi, Kaniwa, Nahoko, Sawada, Jun-ichi, Komamura, Kazuo, Ueno, Kazuyuki, Kamakura, Shiro, Kitakaze, Masafumi, Kitamura, Yutaka, Kamatani, Naoyuki, Minami, Hironobu, Ohtsu, Atsushi, Shirao, Kuniaki, Yoshida, Teruhiko, Saijo, Nagahiro
• Format: Journal Article
• Language: English
• Published: United States 01.06.2004
• Subjects: Aged; Bilirubin - blood; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - metabolism; Female; Genetic Linkage - genetics; Glucuronides - genetics; Glucuronides - metabolism; Glucuronosyltransferase - genetics; Glucuronosyltransferase - metabolism; Haplotypes - genetics; Humans; Japan; Male; Middle Aged; Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Polymorphism, Single Nucleotide - genetics
• ISSN: 0009-9236
• DOI: 10.1016/j.clpt.2004.01.010

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. 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. 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). 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.