Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malaria constitutes one of the major health threats in the tropical and sub-tropical areas of the world. Yet, few advances were made in recent years in revealing the mode of action of the common and most economically affordable antimalarial drugs, the schizontocidal 4-aminoquinolines. Data presented indubitably repudiate the previous notions that these drugs act by either halting the feeding of the parasite on its host erythrocyte cytosol or repressing nucleic acid synthesis due to intercalation into the parasite's DNA. A novel target for drugs is outlined, i.e. they are shown to inhibit in vitro the release of iron from acidified host cell cytosol, consisting mostly of hemoglobin, a process that could provide this trace element to the parasite. Resistance to quinoline-containing drugs is the principal reason for the present resurgence of malaria. Drug-resistant parasites accumulate less of these weak base-like drugs in the acidic digestive vacuoles. A kinetic model is presented, indicating that diminishing drug accumulation is due to decreased vacuolar proton pump activity and is not a result of a putative multidrug resistance (MDR) efflux pump. Findings to date on the molecular biology of parasite mdr genes are reviewed. These indicate no correlation between gene expression or mutations and phenotypic drug resistance. Reversal of parasite drug resistance by relevant compounds in MDR cancer cells seems to involve mechanism(s) different from the inhibition of the MDR pump in cancer cells.
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PMID:Quinoline-containing antimalarials--mode of action, drug resistance and its reversal. An update with unresolved puzzles. 173 99

The anti-malaria drug primaquine is a weak base which accumulates in endosomes in a protonated form and consequently neutralises the endosomal pH. Bafilomycin A1 prevents endosome acidification by inhibiting the vacuolar proton pump. Although both agents neutralise the endosomal pH, only primaquine has a strong inhibitory effect on recycling of endocytosed proteins to the plasma membrane (Van Weert et al. (1995), J. Cell Biol. 130, 821-834). This suggests that primaquine interferes with a parameter, other than endosomal pH, that is essential for membrane recycling. In the presence of 0.3 mM primaquine, endocytosed transferrin-receptors accumulated intracellularly, but not in the additional presence of bafilomycin A1. Thus, at relative low concentrations proton pump-driven accumulation of primaquine in endosomes was required to inhibit membrane recycling, suggesting that the target of primaquine is associated with endosomes. The inhibitory effect of 1 mM primaquine on transferrin receptor recycling was not reversed by the additional presence of bafilomycin A1, indicating that osmotic swelling of endosomes due to accumulation of protonated primaquine could also not explain its effect. To study endosome swelling morphologically, we introduce a novel technique for fluorescent labelling of endosomes involving HRP-catalysed biotinylation. In the presence of 0.2 mM primaquine endosomal vacuoles with diameters up to 2 microm were observed. Endosome swelling was not observed when in addition to primaquine also bafilomycin A1 was present, supporting the notion that vacuolar proton pump activity lowers the dose response for primaquine. Factors that are crucial for membrane recycling and may be affected by primaquine are discussed.
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PMID:Primaquine interferes with membrane recycling from endosomes to the plasma membrane through a direct interaction with endosomes which does not involve neutralisation of endosomal pH nor osmotic swelling of endosomes. 1092 54