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

Abstract

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.

Possibility of quinine transformation in food products: LC–MS and NMR techniques in analysis of quinine derivatives

“…It is worth mentioning that the presented data are in certain contrary to the reports concerning (bio)transformation of quinine and its derivatives [18]. Following [18], these compounds are transformed to demethyl and dearomatic products and to hydroxyl derivatives with hydroxyl group attached to another position in carbon ring of quinine than that indicated in our experiments.…”

“…Following [18], these compounds are transformed to demethyl and dearomatic products and to hydroxyl derivatives with hydroxyl group attached to another position in carbon ring of quinine than that indicated in our experiments. This is obvious as (bio)transformation pathway occurring in living organisms is catalyzed by enzymes and often does not comply with the rules of classical organic synthesis.…”

Mechanism of quinine-dependent monoclonal antibody binding to platelet glycoprotein IIb/IIIa

“…43 Quinine can undergo various cytochrome p450-dependent structural modifications that could result in reactive intermediates capable of linking to protein and acting as haptens to trigger an immune reaction. [48][49][50] A response to quinine-conjugated proteins could explain hapten (quinine)-specific antibodies typically found in patients with quinineinduced thrombocytopenia. 43 The striking difference in serologic behavior of these antibodies, and those that bind to platelets and cause thrombocytopenia, suggests that the two types of antibodies may be induced in quite different ways.…”

Blackwater fever in an uncomplicated Plasmodium falciparum patient treated with dihydroartemisinin-piperaquine

“…Since chloroquine was introduced after World War II supplanting quinine as first-line treatment of uncomplicated malaria, there has been an observed decrease in BWF [ 1 ]. A recent report suggested that metabolism of quinine by the cytochrome P450 3A4 enzyme may be responsible for increasing oxidative stress within erythrocytes, making these cells more vulnerable to haemolysis in those with malaria and/or G6PD deficiency [ 13 ]. The role of artemisinin compounds in such potential oxidant acute haemolysis remains poorly understood [ 14 ].…”