MALARIAL PIGMENT (HAEMOZOIN) - A VERY ACTIVE INERT SUBSTANCE

Malarial pigment (haemozoin; HZ) is generally considered to be a non-t oxic, high-molecular-weight storage form of undigested, toxic, host-ha emoglobin haem. The available information on HZ indicates that it is a very heterogeneous material. Its exact structure, in terms of constit uent proteins (remnants of host globin v. parasite proteins), the type of linkage between the haem moieties (mu-oxo haem dimers further aggr egated by non-covalent hydrophobic bonds v. mutually independent haema tin monomers), iron status in the haem (penta-co-ordinated, high-spin ferriprotoporphyrin IX v. esa-co-ordinated, low-spin ferriprotoporphyr in IX), and composition (beta-haematin-like structure without function ally relevant proteins or other constituents v, a ferriprotoporphyrin- IX core with aggregated proteins and phospholipids of host and parasit e origin) remains a subject of controversy. When ingested by macrophag es, HZ is not inert but affects a number of functional parameters. Cru de pigment, as present in infected erythrocytes and shed after schizon t rupture, map be considered the 'natural diet' ingested by macrophage s in infected blood. It is a powerful source of radicals that may gene rate lipoperoxides and derived, toxic hydroxyaldehydes such as 4-hydro xynonenal (HNE). High concentrations of HNE, which have been detected in HZ-fed macrophages, inhibit protein kinase C (PKC). Complexes betwe en HNE and PKC have also been detected in immunoprecipitated PKC from HZ-fed macrophages. HNE-mediated inhibition of PI(C (and of other, as yet unidentified enzymes and processes) may explain HZ-mediated effect s. 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 inf lammatory proteins 1 alpha and 1 beta, I-IZ-macrophage interactions ma y contribute to the cytokine-mediated manifestations of malaria.