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- Title
Enzymatic Activities of CYP3A4 Allelic Variants on Quinine 3-Hydroxylation In Vitro.
- Authors
Zhou, Xiao-Yang; Hu, Xiao-Xia; Wang, Chen-Chen; Lu, Xiang-Ran; Chen, Zhe; Liu, Qian; Hu, Guo-Xin; Cai, Jian-Ping
- Abstract
Cytochrome P450 3A4 (CYP3A4) enzyme activity is known to show considerable ethnic heterogeneity and inter-individual differences, affecting the outcome of drug treatment. CYP3A4 genetic polymorphisms are believed to be one of the important causes, leading to inter-individual variability in drug metabolism. Quinine is an antipyretic drug with antimalarial properties that is metabolized primarily by CYP3A4. Quinine 3-hydroxylation has been proven as a biomarker reaction for evaluating CYP3A4 ability. Quinine has frequent adverse effects and there are distinct inter-individual differences in quinine sensitivity. The open reading frame for 30 CYP3A4 allelic variants were constructed from wild-type CYP3A4*1A by an overlap extension polymerase chain reaction. Recombinant CYP3A4 variants were expressed using baculovirus-insect cell expression system, and their catalytic activities towards quinine hydroxylation were determined and evaluated. Of the 30 CYP3A4 allelic variants, 23 variants exhibited significantly reduced intrinsic clearance towards quinine, 2 variants showed increased intrinsic clearance for quinine, 2 variants possessed no significant differences towards quinine, compared with CYP3A4*1A, and 3 variants had no detected expression and enzyme activity. Our assessment on the enzymatic activities of CYP3A4 variants towards quinine may contribute to laying an experimental foundation for further clinical studies so as to accelerate the process of determining the associations between genetic variations and clinical phenotypes.
- Subjects
QUININE; CYTOCHROME P-450; DRUG metabolism; POLYMERASE chain reaction; GENETIC polymorphisms; MAGNETIC cores
- Publication
Frontiers in Pharmacology, 2019, pN.PAG
- ISSN
1663-9812
- Publication type
Article
- DOI
10.3389/fphar.2019.00591