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Polymorphisms of CYP2C8 Alter First-Electron Transfer Kinetics and Increase Catalytic Uncoupling
Polymorphisms of CYP2C8 Alter First-Electron Transfer Kinetics and Increase Catalytic Uncoupling
- Source :
- International Journal of Molecular Sciences, Vol 20, Iss 18, p 4626 (2019), International Journal of Molecular Sciences, Volume 20, Issue 18
- Publication Year :
- 2019
- Publisher :
- MDPI AG, 2019.
-
Abstract
- Cytochrome P450 2C8 (CYP2C8) epoxygenase is responsible for the metabolism of over 60 clinically relevant drugs, notably the anticancer drug Taxol (paclitaxel, PAC). Specifically, there are naturally occurring polymorphisms, CYP2C8*2 and CYP2C8*3, that display altered PAC hydroxylation rates despite these mutations not being located in the active site. Herein, we demonstrate that these polymorphisms result in a greater uncoupling of PAC metabolism by increasing the amount of hydrogen peroxide formed per PAC turnover. Anaerobic stopped-flow measurements determined that these polymorphisms have altered first electron transfer kinetics, compared to CYP2C8*1 (wildtype), that suggest electron transfer from cytochrome P450 reductase (CPR) is disfavored. Therefore, these data demonstrate that these polymorphisms affect the catalytic cycle of CYP2C8 and suggest that redox interactions with CPR are disrupted.
- Subjects :
- 0301 basic medicine
Models, Molecular
CYP2C8
education
Hydroxylation
Polymorphism, Single Nucleotide
Catalysis
Article
Inorganic Chemistry
Cytochrome P-450 CYP2C8
Electron Transport
lcsh:Chemistry
03 medical and health sciences
Electron transfer
chemistry.chemical_compound
paclitaxel
0302 clinical medicine
health services administration
Humans
Physical and Theoretical Chemistry
Molecular Biology
lcsh:QH301-705.5
Spectroscopy
reactive oxygen species
cytochrome P450 reductase
biology
Chemistry
Organic Chemistry
Cytochrome P450 reductase
Active site
General Medicine
Metabolism
electron transfer
Antineoplastic Agents, Phytogenic
Computer Science Applications
030104 developmental biology
Biochemistry
Catalytic cycle
lcsh:Biology (General)
lcsh:QD1-999
030220 oncology & carcinogenesis
biology.protein
polymorphisms
Oxidation-Reduction
Cytochrome P450 2C8
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Volume :
- 20
- Issue :
- 18
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....8eebedf5a349e49e35eee0e4e0858b41