Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism

被引:52
作者
Rodriguez-Antona, C. [1 ,2 ]
Niemi, M. [3 ,4 ]
Backman, J. T. [3 ,4 ]
Kajosaari, L. I. [3 ,4 ]
Neuvonen, P. J. [3 ,4 ]
Robledo, M. [1 ]
Ingelman-Sundberg, M. [2 ]
机构
[1] Spanish Natl Canc Ctr CNIO, Human Canc Genet Programme, Hereditary Endocrine Canc Grp, Madrid 28029, Spain
[2] Karolinska Inst, Dept Physiol & Pharmacol, Pharmacogenet Sect, Stockholm, Sweden
[3] Univ Helsinki, Dept Clin Pharmacol, SF-00250 Helsinki, Finland
[4] Helsinki Univ Cent Hosp, Helsinki, Finland
关键词
cytochrome P4502C8 (CYP2C8); haplotype; SNP; paclitaxel; repaglinide;
D O I
10.1038/sj.tpj.6500482
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Cytochrome P450 2C8 (CYP2C8) plays a major role in the metabolism of therapeutically important drugs which exhibit large interindividual differences in their pharmacokinetics. In order to evaluate any genetic influence on this variation, a CYP2C8 phenotype - genotype evaluation was carried out in Caucasians. Two novel CYP2C8 haplotypes, named B and C with frequencies of 24 and 22% in Caucasians, respectively, were identified and caused a significantly increased and reduced paclitaxel 6 alpha-hydroxylation, respectively, as evident from analyses of 49 human liver samples. In healthy white subjects, CYP2C8*3 and the two novel haplotypes significantly influenced repaglinide pharmacokinetics in SLCO1B1c. 521T/C heterozygous individuals: haplotype B was associated with reduced and haplotype C with increased repaglinide AUC (0-infinity). Functional studies suggested -271C>A (CYP2C8*1B) as a causative SNP in haplotype B. In conclusion, two novel common CYP2C8 haplotypes were identified and significantly associated with altered rate of CYP2C8-dependent drug metabolism in vitro and in vivo.
引用
收藏
页码:268 / 277
页数:10
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