Influence of UGT1A9 intronic I399C4T polymorphism on SN-38 glucuronidation in Asian cancer patients


Autoria(s): Chowbay, Balram; Goh, B; Jada, S; Lee, S; Lim, R; Sandanaraj, E; Shu, X; Zhou, Q; Zhou, Shufeng
Data(s)

2008

Resumo

Genetic polymorphisms in hepatically expressed UGT1A1 and UGT1A9 contribute to the interindividual variability i-n irinotecan disposition and toxicity. We screened UGT1A1 (UGT1A1*60, g.−3140G>A, UGT1A1*28 and UGT1A1*6) and UGT1A9 (g.−118(T)9>10 and I399C>T) genes for polymorphic variants in the promoter and coding regions, and the genotypic effect of UGT1A9 I399C>T polymorphism on irinotecan disposition in Asian cancer patients was investigated. Blood samples were collected from 45 patients after administration of irinotecan as a 90 min intravenous infusion of 375 mg/m2 once in every 3 weeks. Genotypic–phenotypic correlates showed that cancer patients heterozygous or homozygous for the I399C>T allele had approximately 2-fold lower systemic exposure to SN-38 (P<0.05) and a trend towards a higher relative extent of glucuronidation (REG) of SN-38 (P>0.05). UGT1A1–1A9 diplotype analysis showed that patients harbouring the H1/H2 (TG6GT10T/GG6GT9C) diplotype had 2.4-fold lower systemic exposure to SN-38 glucuronide (SN-38G) compared with patients harbouring the H1/H5 (TG6GT10T/GG6GT10C) diplotype (P=0.025). In conclusion, this in vivo study supports the in vitro findings of Girard et al. and suggests that the UGT1A9 I399C>T variant may be an important glucuronidating allele affecting the pharmacokinetics of SN-38 and SN-38G in Asian cancer patients receiving irinotecan chemotherapy.

Identificador

http://eprints.qut.edu.au/30907/

Publicador

Nature Publishing Group

Relação

DOI:10.1038/sj.tpj.6500473

Chowbay, Balram, Goh, B, Jada, S, Lee, S, Lim, R, Sandanaraj, E, Shu, X, Zhou, Q, & Zhou, Shufeng (2008) Influence of UGT1A9 intronic I399C4T polymorphism on SN-38 glucuronidation in Asian cancer patients. Pharmacogenomics Journal, 8(3), pp. 174-185.

Fonte

Faculty of Health; Institute of Health and Biomedical Innovation

Palavras-Chave #UGT1A9, Polymorphism, Irinotecan, SN-38, Asians
Tipo

Journal Article