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Enzymatic Activities of CYP3A4 Allelic Variants on Quinine 3-Hydroxylation In Vitro

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 meta...

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Autores principales: Zhou, Xiao-Yang, Hu, Xiao-Xia, Wang, Chen-Chen, Lu, Xiang-Ran, Chen, Zhe, Liu, Qian, Hu, Guo-Xin, Cai, Jian-Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555127/
https://www.ncbi.nlm.nih.gov/pubmed/31214030
http://dx.doi.org/10.3389/fphar.2019.00591
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author Zhou, Xiao-Yang
Hu, Xiao-Xia
Wang, Chen-Chen
Lu, Xiang-Ran
Chen, Zhe
Liu, Qian
Hu, Guo-Xin
Cai, Jian-Ping
author_facet Zhou, Xiao-Yang
Hu, Xiao-Xia
Wang, Chen-Chen
Lu, Xiang-Ran
Chen, Zhe
Liu, Qian
Hu, Guo-Xin
Cai, Jian-Ping
author_sort Zhou, Xiao-Yang
collection PubMed
description 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.
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spelling pubmed-65551272019-06-18 Enzymatic Activities of CYP3A4 Allelic Variants on Quinine 3-Hydroxylation In Vitro Zhou, Xiao-Yang Hu, Xiao-Xia Wang, Chen-Chen Lu, Xiang-Ran Chen, Zhe Liu, Qian Hu, Guo-Xin Cai, Jian-Ping Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2019-05-31 /pmc/articles/PMC6555127/ /pubmed/31214030 http://dx.doi.org/10.3389/fphar.2019.00591 Text en Copyright © 2019 Zhou, Hu, Wang, Lu, Chen, Liu, Hu and Cai http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhou, Xiao-Yang
Hu, Xiao-Xia
Wang, Chen-Chen
Lu, Xiang-Ran
Chen, Zhe
Liu, Qian
Hu, Guo-Xin
Cai, Jian-Ping
Enzymatic Activities of CYP3A4 Allelic Variants on Quinine 3-Hydroxylation In Vitro
title Enzymatic Activities of CYP3A4 Allelic Variants on Quinine 3-Hydroxylation In Vitro
title_full Enzymatic Activities of CYP3A4 Allelic Variants on Quinine 3-Hydroxylation In Vitro
title_fullStr Enzymatic Activities of CYP3A4 Allelic Variants on Quinine 3-Hydroxylation In Vitro
title_full_unstemmed Enzymatic Activities of CYP3A4 Allelic Variants on Quinine 3-Hydroxylation In Vitro
title_short Enzymatic Activities of CYP3A4 Allelic Variants on Quinine 3-Hydroxylation In Vitro
title_sort enzymatic activities of cyp3a4 allelic variants on quinine 3-hydroxylation in vitro
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555127/
https://www.ncbi.nlm.nih.gov/pubmed/31214030
http://dx.doi.org/10.3389/fphar.2019.00591
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