Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism.
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 6alpha-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.
Rodríguez-Antona
C
C
Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden. cristina.rodriguez-antona@cnio.es
Niemi
M
M
Backman
J T
JT
Kajosaari
L I
LI
Neuvonen
P J
PJ
Robledo
M
M
Ingelman-Sundberg
M
M
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D002219:Carbamates / Q000378:metabolism* / Q000494:pharmacology; D065727:Cytochrome P-450 CYP2C8; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics; D006239:Haplotypes / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D017239:Paclitaxel / Q000378:metabolism* / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D044465:White People / Q000235:genetics
D002219:Carbamates; D010880:Piperidines; C072379:repaglinide; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D017239:Paclitaxel