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Effect of Antimalarial Drugs on Plasmodia Cell-Free Protein Synthesis

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      Abstract

      A cell-free system from Plasmodium falciparum able to translate endogenous mRNA was used to determine the effect of artemisinin, chloroquine and primaquine on the protein synthesis mechanism of the parasite. The antimalarial drugs did not inhibit the incorporation of [³H] methionine into parasite proteins even at concentrations higher than the ones found to strongly inhibit the parasite growth. Results clearly indicate that these compounds do not have a direct effect on protein synthesis activity of P. falciparum coded by endogenous mRNA.

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      Cleavage of structural proteins during the assembly of the head of bacteriophage T4.

       U K Laemmli (1970)
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        Access to hematin: the basis of chloroquine resistance.

        The saturable uptake of chloroquine by parasites of Plasmodium falciparum has been attributed to specific carrier-mediated transport of chloroquine. It is suggested that chloroquine is transported in exchange for protons by the parasite membrane Na+/H+ exchanger [J Biol Chem 272:2652-2658 (1997)]. Once inside the parasite, it is proposed that chloroquine inhibits the polymerization of hematin, allowing this toxic hemoglobin metabolite to accumulate and kill the cell [Pharmacol Ther 57:203-235 (1993)]. To date, the contribution of these proposed mechanisms to the uptake and antimalarial activity of chloroquine has not been assessed. Using sodium-free medium, we demonstrate that chloroquine is not directly exchanged for protons by the plasmodial Na+/H+ exchanger. Furthermore, we show that saturable chloroquine uptake at equilibrium is due solely to the binding of chloroquine to hematin rather than active uptake: using Ro 40-4388, a potent and specific inhibitor of hemoglobin digestion and, by implication, hematin release, we demonstrate a concentration-dependent reduction in the number of chloroquine binding sites. An equal number of chloroquine binding sites are found in both resistant and susceptible clones, but the apparent affinity of chloroquine binding is found to correlate with drug activity (r2 = 0.93, p < 0.0001). This completely accounts for both the reduced drug accumulation and activity observed in resistant clones and the "reversal" of resistance produced by verapamil. The data presented here reconcile most of the available biochemical data from studies of the mode of action of chloroquine and the mechanism of chloroquine resistance. We show that the activity of chloroquine and amodiaquine is directly dependent on the saturable binding of the drugs to hematin and that the inhibition of hematin polymerization may be secondary to this binding. The chloroquine-resistance mechanism regulates the access of chloroquine to hematin. Our model is consistent with a resistance mechanism that acts specifically at the food vacuole to alter the binding of chloroquine to hematin rather than changing the active transport of chloroquine across the parasite plasma membrane.
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          Involvement of heme in the antimalarial action of chloroquine.

          When malaria parasites digest hemoglobin, they release FP intracellularly. FP is an oxidized form of heme which is toxic for biological membranes. The parasites are not poisoned when they digest hemoglobin, however, because they sequester FP in hemozoin. In fact, the refractile, dark brown substance in hemozoin is sequestered FP. Chloroquine binds tightly to nonhemozoin FP and, under certain circumstances, enhances its toxicity. In addition, chloroquine interferes with FP sequestration and causes toxic nonhemozoin FP to accumulate to lethal levels in erythrocytes parasitized with malaria parasites. Evidently, this is how chloroquine kills malaria parasites. It is desirable, therefore, to know more about FP sequestration and how it is affected by chloroquine. Malaria parasites possess a catalyst for FP sequestration which is modulated by treatment with quinoline antimalarial drugs such as chloroquine and quinine. Chloroquine treatment causes the activity of the catalyst to decrease by 80 to 90 percent. Quinine treatment has no obvious direct effect on the catalyst for FP sequestration. Nevertheless, quinine treatment antagonizes and reverses the chloroquine-induced loss of ability to sequester FP. The effect of chloroquine treatment also is antagonized by various metabolic inhibitors, including inhibitors of protein biosynthesis such as cycloheximide. These findings indicate that chloroquine, like quinine, does not interact directly with the catalyst for FP sequestration. Instead, they are evidence that chloroquine acts by increasing the amount, accessibility, or reactivity of a regulator of the catalyst for FP sequestration. I propose that chloroquine increases the amount of the regulator, which inactivates the catalyst for FP sequestration, which leads to accumulation of nonhemozoin FP, which binds with high-affinity to chloroquine and which ultimately kills the malaria parasite.
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            Author and article information

            Affiliations
            [1 ] Universidad de Carabobo Venezuela
            Contributors
            Role: ND
            Role: ND
            Role: ND
            Role: ND
            Journal
            mioc
            Memórias do Instituto Oswaldo Cruz
            Mem. Inst. Oswaldo Cruz
            Instituto Oswaldo Cruz, Ministério da Saúde (Rio de Janeiro )
            1678-8060
            April 2002
            : 97
            : 3
            : 377-380
            S0074-02762002000300018
            10.1590/S0074-02762002000300018

            http://creativecommons.org/licenses/by/4.0/

            Product
            Product Information: SciELO Brazil
            Categories
            PARASITOLOGY
            TROPICAL MEDICINE

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