The antimalarial drug quinine interferes with serotonin biosynthesis and action

Farida Islahudin, Sarah M. Tindall, Ian R. Mellor, Karen Swift, Hans Erik Mølager Christensen, Kevin C. F. Fone, Richard J. Pleass, Kang-Nee Ting, Simon V. Avery

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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.
Original languageEnglish
Article number3618
JournalScientific Reports
Volume4
ISSN2045-2322
DOIs
Publication statusPublished - 2014

Keywords

  • MULTIDISCIPLINARY
  • TRYPTOPHAN-HYDROXYLASE
  • KYNURENINE PATHWAY
  • FALCIPARUM-MALARIA
  • RECEPTORS
  • BRAIN
  • DEPLETION
  • BEHAVIOR
  • PROLIFERATION
  • INHIBITION
  • PLASMA
  • malaria Malaria (MeSH) blood and lymphatic disease, parasitic disease drug therapy, symptom
  • Fungi Plantae (Fungi, Microorganisms, Nonvascular Plants, Plants) - Ascomycetes [15100] Saccharomyces cerevisiae species
  • Fungi Plantae (Fungi, Microorganisms, Nonvascular Plants, Plants) - Fungi Imperfecti or Deuteromycetes [15500] Candida albicans species
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] SHSY5Y cell line cell_line human neuroblastoma cells
  • neurotransmitter serotonin-5 5-HT receptor synthesis
  • quinine 130-95-0 antiinfective-drug, antiparasitic-drug
  • tryptophan 73-22-3
  • tryptophan hydroxylase TPH2 9037-21-2 EC 1.14.16.4
  • 02508, Cytology - Human
  • 10060, Biochemistry studies - General
  • 10064, Biochemistry studies - Proteins, peptides and amino acids
  • 12512, Pathology - Therapy
  • 15002, Blood - Blood and lymph studies
  • 15004, Blood - Blood cell studies
  • 15006, Blood - Blood, lymphatic and reticuloendothelial pathologies
  • 22002, Pharmacology - General
  • 22005, Pharmacology - Clinical pharmacology
  • 36008, Medical and clinical microbiology - Mycology
  • 38502, Chemotherapy - General, methods and metabolism
  • 38510, Chemotherapy - Antiparasitic agents
  • 60502, Parasitology - General
  • 60504, Parasitology - Medical
  • Human Medicine, Medical Sciences
  • plasma blood and lymphatics
  • Hematology
  • Parasitology
  • Pharmacology

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