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

Marcsisin S.R., Jin X., Bettger T., McCulley N., Sousa J.C., Shanks G.D., Tekwani B.L., Sahu R., Reichard G.A., Sciotti R.J., Melendez V. and Pybus B.S. (2013) CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC-MS analysis: A possible metabolic link to blackwater fever. Malaria Journal, 12 1: 214.1-214.8. doi:10.1186/1475-2875-12-214


Author Marcsisin S.R.
Jin X.
Bettger T.
McCulley N.
Sousa J.C.
Shanks G.D.
Tekwani B.L.
Sahu R.
Reichard G.A.
Sciotti R.J.
Melendez V.
Pybus B.S.
Title CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC-MS analysis: A possible metabolic link to blackwater fever
Journal name Malaria Journal   Check publisher's open access policy
ISSN 1475-2875
Publication date 2013-06
Year available 2013
Sub-type Article (original research)
DOI 10.1186/1475-2875-12-214
Open Access Status DOI
Volume 12
Issue 1
Start page 214.1
End page 214.8
Total pages 8
Place of publication London United Kingdom
Publisher BioMed Central
Collection year 2014
Language eng
Formatted abstract
Background:
The 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.

Methods:
Incubations of quinine with CYPs 1A2, 2C9, 2C19, 2D6, and 3A4 were conducted, and the metabolites were characterized by accurate mass UPLC-MS§ssup§E§esup§ analysis. Reactive oxygen species generation was also measured in human erythrocytes incubated in the presence of quinine with and without microsomes.

Results:
The 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.

Conclusions:
Taken 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.
Keyword Blackwater fever
CYP450
Metabolism
Metabolite identification
Quinine
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Public Health Publications
 
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Created: Mon, 05 May 2014, 09:59:37 EST by Ms Kate Rowe on behalf of School of Public Health