HEME IS AN OXIDANT SENSITIZER
Of particular relevance to treating malaria is the fact that Plasmodial trophozoites living inside red blood cells must digest hemoglobin as their preferred protein source. [47a,47b] They accomplish this by ingesting hemoglobin into an organelle known as the “acid food vacuole”. [47c-47h] Incidently, the high concentration of acid in this organelle could serve as an additional site of conversion of chlorite (ClO2-) to the more active chlorine dioxide (ClO2) right inside the parasite. Furthermore, Plasmodia consume 50 to 100 times more glucose than noninfected red blood cells most of which is metabolized to lactic acid a known activator of chlorite. [48a-48b]
Next falcipain (a hemoglobin digesting enzyme) hydrolyzes hemoglobin protein to release its nutritional amino acids. [49a-49e] A necessary byproduct of this digestion is the release of 4 heme molecules from each hemoglobin molecule digested. Free heme (also known as ferriprotoporphyrin IX) is redox active and can react with ambient oxygen (O2), an abundance of which is always present in red blood cells. This produces superoxide radical (*OO-), hydrogen peroxide (H2O2) and other reactive oxidant toxic species (ROTS). [50a-50bb]. These can rapidly poison the parasite internally. To protect themselves against this dangerous side-effect of eating blood protein, Plasmodia must maintain a high reductant capacity (an abundance of reduced thiols and NADPH) to quench these ROTS. This is their main mechanism of antioxidant defense. [51a-51n] Plasmodia must also rapidly and continuously eliminate heme , which is accomplished by two methods.
1) heme is polymerized producing hemozoin. [52a-52k]
2) heme is metabolized in a detoxification process that requires reduced glutathione (GSH). [53a,53b]
Therefore any method (especially exposure to oxidants) which limits the availability of reduced glutathione (GSH) will cause a toxic build up of heme and of ROTS inside the parasite cells. Sodium chlorite and chlorine dioxide (the exact agents present in the acidified sodium chlorite treatment) readily oxidize glutathione. [54a,54b] Therefore, a rapid killing of Plasmodia upon taking acidified sodium chlorite orally should be expected.