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Malaria pigment (haemozoin, HZ) is the detoxification product of haemoglobin-derived haem of intraerythrocytic malaria parasites. At schizont rupture, haemozoin accumulates inside host phagocytic cells. The chemical structure and the spectroscopic characteristics of haemozoin are identical to those of beta-haematin (BH), a synthetic pigment obtained from Ferriprotoporphyrin IX (Fe (III) PPIX) in acidic conditions. The process of BH formation is the target of quinoline antimalarials. Here, we summarise the results of our studies on the ultrastructural characteristics, biological and pharmacological relevance of synthetic vs. native haemozoin. 1) By electron microscopy, native HZ and synthetic BH appear as dark brown crystals, morphologically indistinguishable and are internalised by phagocytes at the same extent. 2) Both HZ and BH modulate the production of cytokines (TNF and NO) and increase the susceptibility to lipid peroxidation of mouse or human phagocytes. The antioxidant status of the phagocytes regulates the susceptibility to BH/HZ-mediated effects. 3) The process of BH formation from Fe(III)PPIX, hence haem detoxification, can be inhibited by electrochemically-reduced, Fe(II)PPIX molecules. Maintaining iron in the reduced state can thus be considered a new pharmacological target. This was confirmed by the observation that thiol-reducing agents (NAC, cystein) were able to inhibit BH formation and were toxic to parasites in vitro.

Type

Journal article

Journal

Parassitologia

Publication Date

12/2001

Volume

43 Suppl 1

Pages

45 - 49

Addresses

Istituto di Microbiologia, Università di Milano, Via Pascal 36, 20133 Milano, Italy. donatella.taramelli@unimi.it

Keywords

Phagocytes, Animals, Humans, Mice, Plasmodium, Nitric Oxide, Thiobarbituric Acid Reactive Substances, Tumor Necrosis Factor-alpha, Hemeproteins, Antimalarials, Microscopy, Electron, Crystallography, X-Ray, Spectrophotometry, Infrared, Protein Conformation, Oxidative Stress, Solubility, Models, Molecular, Pigments, Biological