Malarial pigment (haemozoin): a very active 'inert' substance

Malarial pigment (haemozoin; HZ) is generally considered to be a non-toxic, high-molecular-weight storage form of undigested, toxic, host-haemoglobin haem. The available information on HZ indicates that it is a very heterozygous material. Its exact structure, in terms of constituent proteins (remnants of host globin v. parasite proteins), the type of linkage between the haem moieties (mu-oxo haem dimers further aggregated by non-covalent hydrophobic bonds v. mutually independent haematin monomers), iron status in the haem (penta-co-ordinated, high-spin ferriprotoporphyrin IX v. esa-co-ordinated, low-spin ferriprotoporphyrin IX), and compositions (beta-haematin-like structure without functionally relevant proteins or other constituents v. a ferriprotoporphyrin-IX core with aggregated proteins and phospholipids of host and parasite origin) remains a subject of controversy. When investigated by macrophages, HZ is not inert but affects a number of functional parameters. Crude pigment, as present in infected erythrocytes and shed after schizont rupture, may be considered the 'natural diet' ingested by macrophages in infected blood. It is a powerful source of radicals that may generate lipoperoxides and derived, toxic hydroxyaldehydes such as 4-hydroxynonenal (HNE). High concentrations of HNE, which have been detected in HZ-fed macrophages, inhibit protein kinase C (PKC). Complexes between HNE and PKC have also been detected in immunoprecipitated PKC from HZ-fed macrophages. HNE-mediated inhibition of PKC (and of other, as yet unidentified enzymes and processes) may explain HZ-mediated effects. HZ-mediated inhibition of NADPH-oxidase, the enzyme responsible for oxidative bursts, may only be partially explained by PKC inhibition. As Hz-laden human and murine macrophages produce increased amounts of tumour necrosis factor-alpha, interleukins 1 and 6, and macrophage inflammatory proteins 1 alpha and 1 beta, HZ-macrophage interactions may contribute to the cytokine-mediated manifestations of malaria.