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.