CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC-MS analysis: a possible metabolic link to blackwater fever

Malaria Journal

Research

G Dennis Shanks¹  Brandon S Pybus²  Nicholas McCulley²  Richard J Sciotti²  Sean R Marcsisin²  Jason C Sousa²  Gregory A Reichard²  Xiannu Jin²  Theresa Bettger²  Victor Melendez²  Babu L Tekwani³  Rajnish Sahu³ 

[1] Australian Army Malaria Institute, Gallipoli BarracksEnoggera, 4051, QLD, Australia;Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 20910, Silver Spring, MD, USA;National Center for Natural Products Research, School of Pharmacy, University of Mississippi, 38677, Oxford, MS, USA;

关键词: Quinine;    Blackwater fever;    Metabolism;    CYP450;    Metabolite identification;   

DOI  :  10.1186/1475-2875-12-214

 received in 2013-04-19, accepted in 2013-06-11,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundThe naturally occurring alkaloid drug, quinine is commonly used for the treatment of severe malaria. Despite centuries of use, its metabolism is still not fully understood, and may play a role in the haemolytic disorders associated with the drug.MethodsIncubations of quinine with CYPs 1A2, 2C9, 2C19, 2D6, and 3A4 were conducted, and the metabolites were characterized by accurate mass UPLC-MSE analysis. Reactive oxygen species generation was also measured in human erythrocytes incubated in the presence of quinine with and without microsomes.ResultsThe metabolites 3-hydroxyquinine, 2’-oxoquininone, and O-desmethylquinine were observed after incubation with CYPs 3A4 (3-hydroxyquinine and 2’-oxoquininone) and 2D6 (O-desmethylquinine). In addition, multiple hydroxylations were observed both on the quinoline core and the quinuclidine ring system. Of the five primary abundance CYPs tested, 3A4, 2D6, 2C9, and 2C19 all demonstrated activity toward quinine, while 1A2 did not. Further, quinine produced robust dose-dependent oxidative stress in human erythrocytes in the presence of microsomes.ConclusionsTaken in context, these data suggest a CYP-mediated link between quinine metabolism and the poorly understood haemolytic condition known as blackwater fever, often associated with quinine ingestion.

【 授权许可】

Unknown   
© Marcsisin et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.