Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation - PubMed (original) (raw)
Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation
H-J Xie et al. Pharmacogenomics J. 2003.
Abstract
The role of polymorphic CYP2B6 in cyclophosphamide (CPA) bioactivation was investigated in human liver microsomes. A total of 67 human liver specimens were first genotyped with respect to the CYP2B6*5 and CYP2B6*6 variant alleles. CYP2B6 apoprotein levels in 55 liver microsomal preparations were assessed by immunoblotting. 4-Hydroxy-CPA and hydroxy-bupropion were quantified by using HPLC and LC-MS, respectively. 7-Ethoxy-4-trifluoromethyl coumarin O-deethylase activity was measured fluorometrically. The frequencies of CYP2B6*5 and CYP2B6*6 mutant alleles were 9.0 and 16.4%, respectively. CYP2B6 protein expression was detected in 80% of the samples, with a large variation (0.003-2.234, arbitrary units). There was a high correlation between CYP2B6 apoprotein content and CPA 4-hydroxylation (n=55, r=0.81, P<0.0001). When based on the CYP2B6 apoprotein levels, the *6 carriers had significantly higher CPA 4-hydroxylation (P<0.05). CPA 4-hydroxylation also correlated significantly with other CYP2B6-specific reactions (n=20, P<0.0001). V(max) and K(m) for CPA 4-hydroxylation in recombinant CYP2B6 enzyme were 338 nmol/min/nmol enzyme and 1.4 mM, respectively. CYP2B6 showed much higher in vitro intrinsic clearance than previously observed in recombinant CYP2C19 and CYP2C9 variants in yeast expression system. Our results demonstrate that the polymorphic CYP2B6 is a major enzyme in the bioactivation of CPA. Moreover, we identified a strong impact of CYP2B6*6 on CPA 4-hydroxylation.
Similar articles
- Pharmacogenetics of cyclophosphamide in patients with hematological malignancies.
Xie H, Griskevicius L, Ståhle L, Hassan Z, Yasar U, Rane A, Broberg U, Kimby E, Hassan M. Xie H, et al. Eur J Pharm Sci. 2006 Jan;27(1):54-61. doi: 10.1016/j.ejps.2005.08.008. Epub 2005 Sep 23. Eur J Pharm Sci. 2006. PMID: 16183265 Clinical Trial. - Impact of CYP2B6 polymorphism on hepatic efavirenz metabolism in vitro.
Desta Z, Saussele T, Ward B, Blievernicht J, Li L, Klein K, Flockhart DA, Zanger UM. Desta Z, et al. Pharmacogenomics. 2007 Jun;8(6):547-58. doi: 10.2217/14622416.8.6.547. Pharmacogenomics. 2007. PMID: 17559344 - [Cyclophosphamide and CYP2B6].
Torimoto Y, Kohgo Y. Torimoto Y, et al. Gan To Kagaku Ryoho. 2008 Jul;35(7):1090-3. Gan To Kagaku Ryoho. 2008. PMID: 18633247 Japanese. - Cytochrome P450 2B6: function, genetics, and clinical relevance.
Turpeinen M, Zanger UM. Turpeinen M, et al. Drug Metabol Drug Interact. 2012;27(4):185-97. doi: 10.1515/dmdi-2012-0027. Drug Metabol Drug Interact. 2012. PMID: 23152403 Review. - Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6.
Mo SL, Liu YH, Duan W, Wei MQ, Kanwar JR, Zhou SF. Mo SL, et al. Curr Drug Metab. 2009 Sep;10(7):730-53. doi: 10.2174/138920009789895534. Curr Drug Metab. 2009. PMID: 19702527 Review.
Cited by
- Parthenolide enhances the metronomic chemotherapy effect of cyclophosphamide in lung cancer by inhibiting the NF-kB signaling pathway.
Cai Z, Gao L, Hu K, Wang QM. Cai Z, et al. World J Clin Oncol. 2024 Jul 24;15(7):895-907. doi: 10.5306/wjco.v15.i7.895. World J Clin Oncol. 2024. PMID: 39071467 Free PMC article. - Correlation of Genetic Polymorphism of CYP3A5 to Cyclophosphamide Efficacy and Toxicity in Rhabdomyosarcoma Pediatric Egyptian Cancer Patients.
ElShereef CE, Zaki HF, Badary OA, Kamal S, Nagy M, Makhlouf D, Kamal M, Elnadi I, A Abdelshafi S, Abou El Naga S, Saber MM. ElShereef CE, et al. Asian Pac J Cancer Prev. 2024 Jul 1;25(7):2445-2455. doi: 10.31557/APJCP.2024.25.7.2445. Asian Pac J Cancer Prev. 2024. PMID: 39068579 Free PMC article. - Association between gene polymorphisms in the cyclophosphamide metabolism pathway with complications after haploidentical hematopoietic stem cell transplantation.
Muñiz P, Andrés-Zayas C, Carbonell D, Chicano M, Bailén R, Oarbeascoa G, Suárez-González J, Gómez Centurión I, Dorado N, Gallardo D, Anguita J, Kwon M, Díez-Martín JL, Martínez-Laperche C, Buño I. Muñiz P, et al. Front Immunol. 2022 Sep 23;13:1002959. doi: 10.3389/fimmu.2022.1002959. eCollection 2022. Front Immunol. 2022. PMID: 36211438 Free PMC article. - Quantitative Prediction of Drug Interactions Caused by Cytochrome P450 2B6 Inhibition or Induction.
Di Paolo V, Ferrari FM, Poggesi I, Quintieri L. Di Paolo V, et al. Clin Pharmacokinet. 2022 Sep;61(9):1297-1306. doi: 10.1007/s40262-022-01153-y. Epub 2022 Jul 20. Clin Pharmacokinet. 2022. PMID: 35857278 - Pharmacogenetics of Breast Cancer Treatments: A Sub-Saharan Africa Perspective.
Nthontho KC, Ndlovu AK, Sharma K, Kasvosve I, Hertz DL, Paganotti GM. Nthontho KC, et al. Pharmgenomics Pers Med. 2022 Jun 21;15:613-652. doi: 10.2147/PGPM.S308531. eCollection 2022. Pharmgenomics Pers Med. 2022. PMID: 35761855 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases