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The antimalarial drug quinine interferes with serotonin biosynthesis and action

Islahudin, Farida; Tindall, Sarah M.; Mellor, Ian R.; Swift, Karen; Christensen, Hans E.M.; Fone, Kevin C.F.; Pleass, Richard J.; Avery, Simon V.

Authors

Farida Islahudin

Sarah M. Tindall

IAN MELLOR ian.mellor@nottingham.ac.uk
Assistant Professor

Karen Swift

Hans E.M. Christensen

KEVIN FONE KEVIN.FONE@NOTTINGHAM.AC.UK
Professor of Neuroscience

Richard J. Pleass

Simon V. Avery



Abstract

The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmitter serotonin (5-HT), here we test the hypothesis that quinine disrupts serotonin function. Quinine inhibited serotonin-induced proliferation of yeast as well as human (SHSY5Y) cells. One possible cause of this effect is through inhibition of 5-HT receptor activation by quinine, as we observed here. Furthermore, cells exhibited marked decreases in serotonin production during incubation with quinine. By assaying activity and kinetics of the rate-limiting enzyme for serotonin biosynthesis, tryptophan hydroxylase (TPH2), we showed that quinine competitively inhibits TPH2 in the presence of the substrate tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells.

Citation

Islahudin, F., Tindall, S. M., Mellor, I. R., Swift, K., Christensen, H. E., Fone, K. C., …Avery, S. V. (2014). The antimalarial drug quinine interferes with serotonin biosynthesis and action. Scientific Reports, 4(3618), https://doi.org/10.1038/srep03618

Journal Article Type Article
Acceptance Date Dec 10, 2013
Publication Date Jan 9, 2014
Deposit Date Feb 27, 2017
Publicly Available Date Feb 27, 2017
Journal Scientific Reports
Print ISSN 2045-2322
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 4
Issue 3618
DOI https://doi.org/10.1038/srep03618
Keywords drug development, enzyme mechanisms, malaria, mechanism of action
Public URL http://eprints.nottingham.ac.uk/id/eprint/40885
Publisher URL http://www.nature.com/articles/srep03618
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Islahudin et al (2014) Nature Sci. Rep. published pdf.pdf (502 Kb)
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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