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

doi:10.1038/srep03618

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

Department of Chemistry

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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 language	English
Article number	3618
Journal	Scientific Reports
Volume	4
ISSN	2045-2322
DOIs	https://doi.org/10.1038/srep03618
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "The antimalarial drug quinine interferes with serotonin biosynthesis and action",

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.",

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author = "Farida Islahudin and Tindall, {Sarah M.} and Mellor, {Ian R.} and Karen Swift and Christensen, {Hans Erik M{\o}lager} and Fone, {Kevin C. F.} and Pleass, {Richard J.} and Kang-Nee Ting and Avery, {Simon V.}",

year = "2014",

doi = "10.1038/srep03618",

language = "English",

volume = "4",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - The antimalarial drug quinine interferes with serotonin biosynthesis and action

AU - Islahudin, Farida

AU - Tindall, Sarah M.

AU - Mellor, Ian R.

AU - Swift, Karen

AU - Christensen, Hans Erik Mølager

AU - Fone, Kevin C. F.

AU - Pleass, Richard J.

AU - Ting, Kang-Nee

AU - Avery, Simon V.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - MULTIDISCIPLINARY

KW - TRYPTOPHAN-HYDROXYLASE

KW - KYNURENINE PATHWAY

KW - FALCIPARUM-MALARIA

KW - RECEPTORS

KW - BRAIN

KW - DEPLETION

KW - BEHAVIOR

KW - PROLIFERATION

KW - INHIBITION

KW - PLASMA

KW - malaria Malaria (MeSH) blood and lymphatic disease, parasitic disease drug therapy, symptom

KW - Fungi Plantae (Fungi, Microorganisms, Nonvascular Plants, Plants) - Ascomycetes [15100] Saccharomyces cerevisiae species

KW - Fungi Plantae (Fungi, Microorganisms, Nonvascular Plants, Plants) - Fungi Imperfecti or Deuteromycetes [15500] Candida albicans species

KW - Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] SHSY5Y cell line cell_line human neuroblastoma cells

KW - neurotransmitter serotonin-5 5-HT receptor synthesis

KW - quinine 130-95-0 antiinfective-drug, antiparasitic-drug

KW - tryptophan 73-22-3

KW - tryptophan hydroxylase TPH2 9037-21-2 EC 1.14.16.4

KW - 02508, Cytology - Human

KW - 10060, Biochemistry studies - General

KW - 10064, Biochemistry studies - Proteins, peptides and amino acids

KW - 12512, Pathology - Therapy

KW - 15002, Blood - Blood and lymph studies

KW - 15004, Blood - Blood cell studies

KW - 15006, Blood - Blood, lymphatic and reticuloendothelial pathologies

KW - 22002, Pharmacology - General

KW - 22005, Pharmacology - Clinical pharmacology

KW - 36008, Medical and clinical microbiology - Mycology

KW - 38502, Chemotherapy - General, methods and metabolism

KW - 38510, Chemotherapy - Antiparasitic agents

KW - 60502, Parasitology - General

KW - 60504, Parasitology - Medical

KW - Human Medicine, Medical Sciences

KW - plasma blood and lymphatics

KW - Hematology

KW - Parasitology

KW - Pharmacology

U2 - 10.1038/srep03618

DO - 10.1038/srep03618

M3 - Journal article

C2 - 24402577

SN - 2045-2322

VL - 4

JO - Scientific Reports

JF - Scientific Reports

M1 - 3618

ER -

The antimalarial drug quinine interferes with serotonin biosynthesis and action

Abstract

Keywords

UN SDGs

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