Academic journal article Environmental Health Perspectives

Monensin Improves the Effectiveness of Meso-Dimercaptosuccinate When Used to Treat Lead Intoxication in Rats

Academic journal article Environmental Health Perspectives

Monensin Improves the Effectiveness of Meso-Dimercaptosuccinate When Used to Treat Lead Intoxication in Rats

Article excerpt

Among divalent cations, the ionophore monensin shows high activity and selectivity for the transport of lead ions ([Pb.sup.2+]) across phuspholipid membranes. When coadministered to rats that were receiving meso-dimercaptosuccinate for treatment of Pb intoxication, monensin significantly increased the amount of Pb removed from femur, brain, and heart. It showed a tendency to increase Pb removal from liver and kidney but had no effect of this type in skeletal muscle. Tissue levels of several physiologic (calcium, cobalt, copper, iron, magnesium, manganese, molybdenum, zinc) and nonphysiologic (arsenic, cadmium, chromium, nickel, strontium) elements were also determined after the application of these compounds. Among the physiologic elements, a number of significant changes were seen, including both rising and falling values. The size of these changes was typically around 20% compared with control values, with the largest examples seen in femur. These changes often tended to reverse those of similar size that had occurred during Pb administration. Among the nonphysiologic elements, which were present in trace amounts, the changes were smaller in number but larger in size. None of these changes appears likely to be significant in terms of toxicity, and there were no signs of overt toxicity under any of the conditions employed. Monensin may act by cotransporting [Pb.sup.2+] and OH- ions out of cells, in exchange for external sodium ions. The net effect would be to shuttle intracellular [Pb.sup.2+] to extracellular dimercaptosuccmic acid thereby enhancing its effectiveness. Thus, monensin may be useful for the treatment of Pb intoxication when applied in combination with hydrophilic [Pb.sup.2+] chelators. Key words: chelation therapy, DMSA, heavy metal intoxication, ICP mass spectroscopy, ionophores, monensin, Pb, [Pb.sup.2+] transport, trace metal cations. doi:10.1289/ehp.8279 available via http://dx.doi.org/ [Online 29 September 2005]

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Several polyether ionophores, including A23187, ionomycin, monensin, and nigericin, have been shown to transport lead ions ([Pb.sup.2+]) across phospholipid bilayers and to form stable complexes with [Pb.sup.2+] in homogeneous solution (Erdahl et al. 2000; Hamidinia et al. 2002, 2004). Among this group, the order of transport activity is ionomycin > nigericin > monensin > A23187, whereas the order of selectivity, compared with other divalent cations, is nigericin > monensin > ionomycin > A23187. Ionomycin can be used to load cultured cells and to deplete them of [Pb.sup.2+] (Erdahl et al. 2000), and effects of monensin on Pb dynamics in rats have also been investigated (Hamidinia et al. 2002). In the latter area it was found that simultaneous administration of monensin in feed and [Pb.sup.2+] in drinking water lowers the prevailing concentration of Pb in blood and decreases the accumulation of Pb in several soft tissues and in bone. Feeding monensin after a period of [Pb.sup.2+] administration was furthermore effective at accelerating the clearance of Pb from brain, liver, kidney and bone, with the monensin-related increment being found in feces, as opposed to the Pb excreted spontaneously, which included a component found in urine (Hamidinia et al. 2002).

The actions of monensin on Pb dynamics in rats suggest the possibility of using ionophores in the treatment of human Pb intoxication. At present, the ongoing and widespread problem of Pb intoxication is treated first by removing the individual from the Pb-contaminated environment and thereafter by administering a [Pb.sup.2+] chelating agent. meso-Dimercaptosuccinic acid (DMSA) is the most commonly used agent at present, in part because it can be administered orally and is well tolerated (Cory-Slechta 1988; Graziano et al. 1985). DMSA is a water-soluble compound that forms a strong complex with [Pb.sup.2+] in blood, which is thereafter secreted via the kidney. EDTA and other chelating agents are used in a similar way to treat Pb intoxication (Goyer et al. …

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