IRON-DEPENDENT FREE-RADICAL GENERATION FROM THE ANTIMALARIAL AGENT ARTEMISININ (QINGHAOSU)

Artemisinin is an important new antimalarial agent containing a bridge d endoperoxide. The in vitro antimalarial activity of an artemisinin d erivative, 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 chela tor, deferoxamine-hydroxyethylstarch. A combination of artemisinin and hemin oxidizes erythrocyte membrane thiols in vitro, and this oxidati on is also inhibited by an iron chelator. Thus, iron plays a role in t he mechanisms of action and toxicity of artemisinin. The combination o f artemisinin and hemin also decreases erythrocyte deformability. Iron probably catalyzes the generation of free radicals from artemisinin s ince alpha-tocopherol antagonizes the thiol-oxidizing activity of arte misinin and since a spin-trapped free radical signal can be seen by el ectron paramagnetic resonance only when artemisinin is incubated in th e presence of iron.