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.

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., Pleass, R. J., & 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
• 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: https://nottingham-repository.worktribe.com/output/721995
• Publisher URL: http://www.nature.com/articles/srep03618
• Contract Date: Feb 27, 2017