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

• Type of Material: Article
• Authors: Jack Arbiser, Emory University; Kraeft Stine-Kathrein, Dana-Farber Cancer Institute; Robert van Leeuwen,, University of Leiden; Selwyn Hurwitz, Emory University; Martin Selig, Harvard Medical School; G. R. Dickersin, Harvard Medical School; Alan Flint, Children's Hospital, Boston; H. Randolph Byers, Boston University School of Medicine; Lan Bo Chen, Dana-Farber Cancer Institute
• Language: English
• Date: 1998-10
• Publisher: Feinstein Institute for Medical Research
• Publication Version: Final Published Version
• Copyright Statement: ©1998 The Picower Institute Press. Molecular Medicine is an open access biomedical research journal seeking insight into the cellular and molecular basis of disease.
• Final Published Version (URL): http://molmed.org/home
• Title of Journal or Parent Work: Molecular Medicine
• ISSN: 1076-1551
• Volume: 4
• Issue: 10
• Start Page: 665
• End Page: 670
• Grant/Funding Information: J.L.A. was supported by grants from the Dennatology Foundation, Howard Hughes Medical Institute, the Thomas B. Fitzpatrick Research Award from the KAO Corporation, and grant R03AR44947 from the National Institutes of Health.
• Research Categories: Biology, Molecular; Health Sciences, Pathology

Abstract

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.