Iron-dependent free radical generation from the antimalarial agent artemisinin (qinghaosu)

Abstract

Artemisinin is an important new antimalarial agent containing a bridged endoperoxide. The in vitro antimalarial activity of an artemisinin derivative, arteether, is antagonized by two iron chelators, pyridoxal benzoylhydrazone and 1,2-dimethyl-3-hydroxypyrid-4-one. Similarly, the acute toxicity of artemisinin in mice is antagonized by another chelator, deferoxamine-hydroxyethylstarch. A combination of artemisinin and hemin oxidizes erythrocyte membrane thiols in vitro, and this oxidation is also inhibited by an iron chelator. Thus, iron plays a role in the mechanisms of action and toxicity of artemisinin. The combination of artemisinin and hemin also decreases erythrocyte deformability. Iron probably catalyzes the generation of free radicals from artemisinin since ao-tocopherol antagonizes the thiol-oxidizing activity of artemisinin and since a spin-trapped free radical signal can be seen by electron paramagnetic resonance only when artemisinin is incubated in the presence of iron.Malaria remains an important global health problem, affecting an estimated 270 million people per year and killing 1 to 2 million people per year (47). Resistance to currently used antimalarial drugs such as chloroquine, quinine, mefloquine, and Fansidar is spreading rapidly (47). Thus, there is a great need for new antimalarial agents.The antimalarial agent artemisinin (qinghaosu) was isolated in 1972 from Artemisia annua, an ancient Chinese herbal remedy for fever (for a review, see reference 26). Several artemisinin derivatives are currently undergoing phase I and II clinical studies, including artemether, arteether, and artesunate, which are the methyl ether, ethyl ether, and succinate esters, respectively, of dihydroartemisinin. Artemisinin and its derivatives have been widely used for the therapy of malaria in China, Vietnam, Thailand, and Myanmar; over 2 million doses of artemether have been administered in China alone. Artemisinin-type antimalarial agents are particularly useful against chloroquine-resistant Plasmodium falciparum strains and cerebral malaria (47).

Reaction of artemisinin with haemoglobin: implications for antimalarial activity

“…This cleavage of the peroxide is mediated by iron, which makes iron a necessity in the early onset of artemisinin action [32,33]. In fact, the oxidizing effects of artemisinin on parasitic membranes are greatly enhanced in the presence of haem [34], and haem itself is known to react with artemisinin [9,22,35].…”

Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins

“…Formation of carbon-centered free radicals has been suggested. 5,[8][9][10][11][12] A recent meta-analysis revealed that ART-containing regimens substantially reduce treatment failure compared to standard antimalarial treatments. 13 ART can significantly prolong the time span of antimalarial treatment efficacy.…”

Artemether administered together with haemin damages schistosomes in vitro

“…With regard to artemisinin and malaria, it is believed that 2 sequential steps ate involved. Activation of artemisinin inside the malarial parasite by heme or other iron systems results in cleavage of endoperoxide bridges and generation of free radicals, and formation of covalent complexes between these free radicals and malaria-specific proteins or specific receptors (MESHNICK et al, 1991(MESHNICK et al, , 1993ZHANG et al, 1992;KAMCHONW~NGPAISAN & MESHNICK, 1996;MESHNICK, 1998;DHINGRA et al, 2000). Both the parent artemisinin compound and its more active derivative artemether (HIEN & WHITE, 1993) are rapidly metabolized to the biologically active dihvdroartemisinin WHITE.…”