Cytochrome P450 Genetic Variations Can Predict mRNA Expression, Cyclophosphamide 4-Hydroxylation, and Treatment Outcomes in Chinese Patients With Non-Hodgkin's Lymphoma.
To investigate the impact of cytochrome P450 (CYP) genetic polymorphisms CYP2B6, CYP2C19, and CYP3A5 on mRNA expression, cyclophosphamide/4-hydroxycyclophosphamide pharmacokinetics, and treatment outcomes of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in Chinese patients with non-Hodgkin's lymphoma, 567 cases were investigated. Plasma concentrations of cyclophosphamide/4-hydroxycyclophosphamide were determined using liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters calculated. The frequencies of CYP2B6*1/*29 and CYP2B6*1/*30 were 18 (3.2%) and 30 (5.3%), respectively. Liver samples with CYP2B6*29/*30, CYP2C19*2, CYP2B6*6, or CYP3A5*3 had significantly lower target mRNA expression. Samples with CYP2B6*6 and/or CYP2C19*2 had lower exposure to 4-hydroxycyclophosphamide, whereas those with CYP2B6*1G/*1H had higher exposure. Multivariate model showed that samples with CYP2C19*2 or CYP2B6 785A>raG had worse treatment response than samples with CYP3A5*3. CYP2C19*2, CYP2B6*6, CYP2B6*29, and CYP2B6*30 were protective factors for toxicity in the multivariate model. The best model for gene-gene interactions for treatment response contained CYP2C19*2, CYP2B6 785A>G, and CYP3A5*3 (cross-validation consistency [CVC], 8/10; P = .0035). The best prediction model for grade 2-4 toxicities had CYP2C19*2, CYP2B6 785A>G, and 516 G>T (CVC, 10/10; P < .0001). In previous reports, we were the first to report that the frequency of copy-number variations in CYP2B6 is higher among Chinese than among other ethnic populations. Genetic variations in CYP2B6, CYP2C19, and CYP3A5 dramatically affected the mRNA expression of proteins, the pharmacokinetics of 4-hydroxycyclophosphamide, and the R-CHOP treatment response in Chinese subjects. Patients carrying CYP3A5*3 were more likely to have a better treatment response, whereas patients with CYP2C19*2 or CYP2B6 516G>T, or CYP2B6 785A>G had higher tolerance to treatment.
Department of Pharmacy, Cancer Center of Guangzhou Medical University, Guangzhou, P. R. China.
Wenying
W
Shu
Department of Medical & Molecular Genetics, Guy's Hospital, King's College London, London, UK.
Lingyan
L
Chen
Department of Internal Medicine, Cancer Center of Guangzhou Medical University, Guangzhou, P. R. China.
Xiaoye
X
Hu
Department of Pharmacy, Cancer Center of Guangzhou Medical University, Guangzhou, P. R. China.
Meimei
M
Zhang
Department of Internal Medicine, Cancer Center of Guangzhou Medical University, Guangzhou, P. R. China.
Wensheng
W
Chen
Department of Internal Medicine, Cancer Center of Guangzhou Medical University, Guangzhou, P. R. China.
Lei
L
Ma
Department of Internal Medicine, Cancer Center of Guangzhou Medical University, Guangzhou, P. R. China.
Xiaoyan
X
Liu
Department of Pharmacy, Cancer Center of Guangzhou Medical University, Guangzhou, P. R. China.
Jianing
J
Huang
Department of Pharmacy, Cancer Center of Guangzhou Medical University, Guangzhou, P. R. China.
Tingyuan
T
Pang
Department of Pharmacy, Cancer Center of Guangzhou Medical University, Guangzhou, P. R. China.
Jia
J
Li
School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, P. R. China.
Yu
Y
Zhang
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D044466:Asian People; D003520:Cyclophosphamide / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D022781:Hepatocytes; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System
copy-number variation; cyclophosphamide; cytochrome P450 genes; pharmacogenomics; pharmacokinetics