Toxic heme in sickle cells: an explanation for death of malaria parasites.

In an effort to elucidate a mechanism of genetic resistance to malaria, we asked whether a toxic form of heme is included in the excess of ferriprotoporphyrin IX (FP) which has been reported to accumulate as hemichromes in sickle cells. When FP is bound to certain erythrocytic elements, such as native hemoglobin, it is inaccessible to bind chloroquine with high affinity and is nontoxic. However, when FP is accessible to bind chloroquine with high affinity, it has been demonstrated to be sufficiently free to have membrane toxicity and, under certain conditions, to lyse Plasmodium falciparum parasites.

Ferriprotoporphyrin IX: a mediator of the antimalarial action of oxidants and 4-aminoquinoline drugs.

Ferriprotoporphyrin IX (FP) is released from hemoglobin by oxidative denaturation or by proteolytic degradation. FP added exogenously to cells or released intracellularly is a lytic toxin. Chloroquine enhances the accumulation of exogenous FP in cellular membranes and potentiates its lytic effect.

Intracellular ferriprotoporphyrin IX is a lytic agent.

Human erythrocytes were treated with menadione to oxidatively denature hemoglobin and release ferriprotoporphyrin IX (ferriheme, FP) intracellularly. The high affinity of FP for chloroquine was used to detect its release. After incubation for 1 hr at 37 degrees C and pH 7.

Lysis of Plasmodium falciparum by ferriprotoporphyrin IX and a chloroquine-ferriprotoporphyrin IX complex.

Ferriprotoporphyrin IX (FP) and a chloroquine-FP complex lysed isolated Plasmodium falciparum parasites as judged by decreases in the turbidity of parasite suspensions and by ultrastructural changes. Exposure of parasite suspensions to 50 microM FP or to a complex formed from 50 microM FP and 20 MicroM chloroquine reduced the number of identifiable parasites and caused swelling and loss of internal detail in those that were identifiable. The amount of lysis was dose-dependent over the range of 10 to 50 microM FP.