Clioquinol-zinc chelate: a candidate causative agent of subacute myelo-optic neuropathy

• Published in: Molecular medicine (Cambridge, Mass.) Mass.), 1998-10, Vol.4 (10), p.665-670
• Main Authors: Arbiser, J L, Kraeft, S K, van Leeuwen, R, Hurwitz, S J, Selig, M, Dickersin, G R, Flint, A, Byers, H R, Chen, L B
• Format: Article
• Language: English
• Subjects: Chelating Agents - pharmacology; Clioquinol - pharmacology; Humans; Membrane Potentials - drug effects; Mitochondria - drug effects; Mitochondria - physiology; Myelitis - etiology; Optic Neuritis - etiology; Syndrome; Tumor Cells, Cultured; Zinc - pharmacology
• ISSN: 1076-1551; 1528-3658
• DOI: 10.1007/bf03401927

5-chloro-7-iodo-8-hydroxyquinoline (clioquinol) was used clinically three decades ago as an oral antiparasitic agent and to increase intestinal absorption of zinc in patients with acrodermatitis enteropathica, a genetic disorder of zinc absorption. Use of clioquinol was epidemiologically linked to subacute myelo-optic neuropathy (SMON), characterized by peripheral neuropathy and blindness, which affected 10,000 patients in Japan. Discontinuation of oral clioquinol use led to elimination of SMON, however, the mechanism of how clioquinol induces neurotoxicity is unclear. We tested the effect of clioquinol-metal chelates on neural crest-derived melanoma cells. The effect of clioquinol chelates on cells was further studied by electron microscopy and by a mitochondrial potential-sensitive fluorescent dye. Of the ions tested, only clioquinol-zinc chelate demonstrated cytotoxicity. The cytotoxicity of clioquinol-zinc chelate was extremely rapid, suggesting that its primary effect was on the mitochondria. Electron microscopic analysis demonstrated that clioquinol-zinc chelate caused mitochondrial damage. This finding was further confirmed by the observation that clioquinol-zinc chelate caused a decrease in mitochondrial membrane potential. We demonstrate that clioquinol, in the presence of zinc, is converted to a potent mitochondrial toxin. The phenomenon of clioquinol mediated toxicity appears to be specific to zinc and is not seen with other metals tested. Since clioquinol has been shown to cause increased systemic absorption of zinc in humans, it is likely that clioquinol-zinc chelate was present in appreciable levels in patients with SMON and may be the ultimate causative toxin of SMON.