Bioactivation of cyclophosphamide: the role of polymorphic CYP2C enzymes.
Several-fold differences have been observed among patients in the biotransformation of cyclophosphamide. The aim of this study was to investigate the contribution of CYP2C9 and CYP2C19 and their polymorphisms to the variability of cyclophosphamide activation. The formation of 4-hydroxycyclophosphamide was studied in microsomes from a total of 32 different genotyped human livers, as well as in yeast microsomes expressing different genetic variants of CYP2C9 and CYP2C19. The kinetic data obtained in the yeast system revealed that the intrinsic clearance (V(max)/K(m)) of cyclophosphamide by CYP2C9.2 and CYP2C9.3 samples was approximately threefold lower than that by CYP2C9.1. However, in liver microsomes, there were no statistically significant differences in the intrinsic clearance of 4-hydroxycyclophosphamide formation between the group of seven CYP2C9*1/*1 livers and the remaining nine with one or two variant CYP2C9 alleles ( P>0.7). We found a statistically significant correlation ( r(s)=0.65, P=0.003) between 4-hydroxylation of cyclophosphamide and 5'-hydroxylation of R-omeprazole, a measure of CYP2C19 activity in human liver microsomes ( n=19). No correlation was found between 4-hydroxylation of cyclophosphamide and the formation rate of hydroxycelecoxib, mainly catalysed by CYP2C9 ( r(s)=0.17, P=0.55, n=32). In conclusion, based on the correlation with the formation of R-5'-hydroxyomeprazole, CYP2C19 may partly contribute to the bioactivation of cyclophosphamide in human liver microsomes, while the role of CYP2C9 appears minor.
Griskevicius
Laimonas
L
Department of Medical Laboratory Sciences and Technology, Karolinska Institutet at Huddinge University Hospital, 14186 Stockholm, Sweden.
Yasar
Umit
U
Sandberg
Mia
M
Hidestrand
Mats
M
Eliasson
Erik
E
Tybring
Gunnel
G
Hassan
Moustapha
M
Dahl
Marja-Liisa
ML
D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D000068579:Celecoxib; D003520:Cyclophosphamide / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009853:Omeprazole / Q000378:metabolism; D011110:Polymorphism, Genetic; D011720:Pyrazoles; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D011720:Pyrazoles; D013449:Sulfonamides; D003520:Cyclophosphamide; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000068579:Celecoxib; D009853:Omeprazole