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

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          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.

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          Most cited references41

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          Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects.

          The polymorphic nature of the cytochrome P450 (CYP) genes affects individual drug response and adverse reactions to a great extent. This variation includes copy number variants (CNV), missense mutations, insertions and deletions, and mutations affecting gene expression and activity of mainly CYP2A6, CYP2B6, CYP2C9, CYP2C19 and CYP2D6, which have been extensively studied and well characterized. CYP1A2 and CYP3A4 expression varies significantly, and the cause has been suggested to be mainly of genetic origin but the exact molecular basis remains unknown. We present a review of the major polymorphic CYP alleles and conclude that this variability is of greatest importance for treatment with several antidepressants, antipsychotics, antiulcer drugs, anti-HIV drugs, anticoagulants, antidiabetics and the anticancer drug tamoxifen. We also present tables illustrating the relative importance of specific common CYP alleles for the extent of enzyme functionality. The field of pharmacoepigenetics has just opened, and we present recent examples wherein gene methylation influences the expression of CYP. In addition microRNA (miRNA) regulation of P450 has been described. Furthermore, this review updates the field with respect to regulatory initiatives and experience of predictive pharmacogenetic investigations in the clinics. It is concluded that the pharmacogenetic knowledge regarding CYP polymorphism now developed to a stage where it can be implemented in drug development and in clinical routine for specific drug treatments, thereby improving the drug response and reducing costs for drug treatment.
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            Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria

            Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention. In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics. In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance.
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              Pharmacogenetics, pharmacogenomics, and individualized medicine.

              Individual variability in drug efficacy and drug safety is a major challenge in current clinical practice, drug development, and drug regulation. For more than 5 decades, studies of pharmacogenetics have provided ample examples of causal relations between genotypes and drug response to account for phenotypic variations of clinical importance in drug therapy. The convergence of pharmacogenetics and human genomics in recent years has dramatically accelerated the discovery of new genetic variations that potentially underlie variability in drug response, giving birth to pharmacogenomics. In addition to the rapid accumulation of knowledge on genome-disease and genome-drug interactions, there arises the hope of individualized medicine. Here we review recent progress in the understanding of genetic contributions to major individual variability in drug therapy with focus on genetic variations of drug target, drug metabolism, drug transport, disease susceptibility, and drug safety. Challenges to future pharmacogenomics and its translation into individualized medicine, drug development, and regulation are discussed. For example, knowledge on genetic determinants of disease pathogenesis and drug action, especially those of complex disease and drug response, is not always available. Relating the many gene variations from genomic sequencing to clinical phenotypes may not be straightforward. It is often very challenging to conduct large scale, prospective studies to establish causal associations between genetic variations and drug response or to evaluate the utility and cost-effectiveness of genomic medicine. Overcoming the obstacles holds promise for achieving the ultimate goal of effective and safe medication to targeted patients with appropriate genotypes.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                31 May 2019
                2019
                : 10
                : 591
                Affiliations
                [1] 1The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology , Beijing, China
                [2] 2Department of Pharmacy, Jinhua Central Hospital , Jinhua, China
                [3] 3School of Pharmacy, Wenzhou Medical University , Wenzhou, China
                [4] 4Department of Pharmacy, Wenzhou People’s Hospital , Wenzhou, China
                Author notes

                Edited by: Yurong Lai, Gilead, United States

                Reviewed by: Hyunyoung Jeong, University of Illinois at Chicago, United States; Yvonne Lin, University of Washington, United States

                *Correspondence: Jian-Ping Cai, caijp61@ 123456vip.sina.com

                This article was submitted to Drug Metabolism and Transport, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2019.00591
                6555127
                31214030
                89be8883-ac67-40d4-a1bf-d9daecaae3cf
                Copyright © 2019 Zhou, Hu, Wang, Lu, Chen, Liu, Hu and Cai

                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.

                History
                : 16 February 2019
                : 08 May 2019
                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 48, Pages: 14, Words: 6528
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                cytochrome p450 3a4,drug metabolism,quinine,3-hydroxylation,polymorphism

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