Desferrioxamine

Desferrioxamine B is a siderophore from the Streptomycespilosus bacterium which binds iron(III) [2], As discussed in Chapter 5 the evolution of siderophores, literally iron-carrying molecules, is as a consequence of organisms reliance on iron in 

Two binding sites are commonly found catecholate, as in enterobactin, and hydroxamate, the motif in desferrioxamine B. The resulting complex is targeted by a membrane-bound receptor and captured by the organism. The complex is transported across the cell membrane where the iron is reduced to iron(II), which has a lower affinity for the siderophore, and subsequently decomplexed. 

The high affinity for oxidized iron makes the siderophores ideal candidates for chelation therapy where the body is becoming overwhelmed by iron(III) either through acute poisoning or conditions like haemochromatosis that can occur when patients receive frequent blood transfusions. While enterobactin would seem to be the primary choice it has two major drawbacks its synthesis is complicated and, although both isomers bind iron(III) to the same extent, only the L-isomer has activity in vivo. Consequently desferrioxamine B is the agent of choice. 

2 Copper Imbalance Wilson s Disease andMenke s Syndrome 

In vivo tolerance to copper is quite high, however, deficiency and excess are serious problems. Infants are particularly vulnerable as they take time to assimilate the correct levels and it is known that trace copper from cooking utensils or water pipes can cause childhood cirrhosis. Copper deficiency leads to arterial weakness and heart enlargement. This is probably caused by a decrease in catecholamine neurotransmitters derived from the biosynthesis of adrenaline which requires the copper-containing enzymes phenylalanine hydroxylase, dopamine P-monooxygenase and tyrosinase. 

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A molecule that binds iron through coordinating moieties (e.g., carboxylates or amines). They are used to inhibit iron-catalyzed free radical reactions or to treat iron overload conditions. Desferrioxamine and defer-iprone are two widely used iron chelators. 

Siderophores like desferrioxamine may, therefore, find increasing applications not only in the treatment of iron poisoning and iron-overloaded disease states but also as chemotherapeutic agents, although the possible problems noted above cannot be ignored. 

Rice-Evans, C., Okunade, G. and Khan, R. (1989). The suppression of iron release from activated myoglobin by physiological electron donors and desferrioxamine. Free Rad. Res. Commun. 7, 45-54. 

Gower, J.D., HeaUng, G., FuUer, B.J., Simpkin, S. and Green, C.J. (1989a). Protection against oxidative damage in cold-stored rabbit kidneys by desferrioxamine and indomethacin. Cryobiology 26, 309-317. 

Gower, J., Healing, G. and Green, C.J. (1989c). Measurement by HPLC of desferrioxamine-avaUable iron in rabbit kidneys to assess the effect of ischaemia on the distribution of iron within the total pool. Free Rad. Res. Commun. 5, 291-299. 

Gower, J.D., Ambrose, I.J., Manek, S., Bright, P.S., Dobbin, P.S., Hider, R.C., Goddard, J.G., Thomiley, M.S. and Green, C.J. (1993). The effect of a synthetic hexadentate iron chelator (CP130) and desferrioxamine on rabbit kidneys exposed to cold and warm ischaemia. Agents Actions 40, 96-105. 

Gutteridge, J.M.C., Richmond, R, and HaUiweU, B. (1979). Inhibition of the iron-catalysed formation of hydroxyl radicals from superoxide and of lipid peroxidation by desferrioxamine. Biochem. J. 184, 469-472. 

Gastric mucosal injury induced by non-steroidal antiinflammatory drugs such as aspirin and indomethacin has also been extensively studied, again with somewhat conflicting results. Several studies have shown a protective effect of SOD, catalase, hydroxyurea and desferrioxamine (Takeuchi et al., 1991a Vaananen et al., 1991 Naito et al., 1992). Del Soldato etal. (1985) also found aminopy-rine, thiourea and its derivative, MK 447, and SAZ to be protective. Allopurinol has been shown to be both protective (Takeuchi etal., 1991a) and ineffective (Vaananen etal., 1991). 

Cell culture Damage to small intestinal epithelial cells by XO can be prevented by SOD and desferrioxamine (Ma et al., 1991), whilst that to rat enterocytes, CaCo cells or rabbit colonic epithelial cells by XO can be decreased by catalase (Baker and Baker, 1990 Baker and Campbell, 1991 Kawabe etal., 1992). 

Treatment with iron chelators and a-tocopherol protect against lipid p>eroxidation and hepatocellular injury in iron-overloaded rats (Sharma etal., 1990). When hepatocytes are isolated from rats, which have been pretreated with a-tocopherol, there is a significant reduction in iron-induced lipid peroxidation and improvement in cell viability in vitro (Poli et al., 1985). Similar effects were seen when hepatocytes were incubated with iron chelators (Bacon and Britton, 1990). Treatment of moderately, but not heavily, iron-loaded rats with desferrioxamine in vivo inhibits the pro-oxidant activity of hepatic ultrafiltrates (Britton et al., 1990b). 

Bradley, B., Prowse, S.J., Bauling, P. and Lafierty, K.J. (1986). Desferrioxamine treatment prevents chronic islet allograft damage. Diabetes 35, 550-555. 

These two mechanisms (DNA damage by OH or by activation of nucleases) are not mutually exclusive, i.e. they could both take place (Fig. 13.1). Indeed, there is evidence consistent with the existence of both mechanisms. Their relative importance may depend on the cell type used and on how the oxidative stress is imposed (Halliwell and Aruoma, 1991). For example, chelating agents that bind iron ions into chelates unable to generate OH (such as desferrioxamine. 

Experimental in vitro investigations utilizing liposomal-encapsulated and polyethylene glycol-conjugated SOD and catalase have demonstrated the potential value of such means in countering oxidative asbestos-related diseases (Freeman etal., 1985 Mossman etal., 1986). In addition to using supplementary endogenous antioxidant enzymes, the use of iron chelators like desferrioxamine... 

Beyer, W.F. and Fridovich, I. (1989). Characterization of a superoxide dismutase mimic prepared from desferrioxamine and MnOa. Arch. Biochem. Biophys. 271, 149-156. 

Olivieri, N.F., Koren, G., Hermann, C., Bentur, Y., Chung, D. and Klein, J. (1990). Comparison of oral iron chelator LI and desferrioxamine in iron loaded patients. Lancet 336, 1275-1279. 

Diethylenetriaminepentaacetic acid DFMO al-Difluoromethyl ornithine DFP Diisopropyl fluorophosphate DFX Desferrioxamine DGLA Dihomo-y-linolenic acid DH Delayed hypersensitivity DHA Docosahexaenoic acid DHBA Dihydroxybenzoic acid DHR Delayed hypersensitivity reaction... 

Iron uptake by bacteria at sites of lateral root emergence has been further confirmed using another technique employing 7-nitrobenz-2-oxa-l,3-diazole-desferrioxamine B, which is a derivitized siderophore that becomes fluorescent after it is deferrated (78). In this case, iron uptake from the siderophore ferrox-amine B was a.ssociated primarily with microbially colonized roots, but both plant and iron uptake from this chelate occurred in the regions just behind the root tips. 

V. Solinas, S. Deiana, C. Gessa, C. Pistidda, and R. Rausa, Reduction of the Felll-desferrioxamine-B complexes by caffeic acid a reduction mechanism of biochemical significance. Soil. Biol. Biochem. 275 649 (1996). 

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