title: Clioquinol-zinc chelate: a candidate causative agent of subacute myelo-optic neuropathy.
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.
  
  
  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.
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia, USA. jarbise@emory.edu
authors.forename: J L
authors.initials: JL
authors.lastname: Arbiser
authors.forename: S K
authors.initials: SK
authors.lastname: Kraeft
authors.forename: R
authors.initials: R
authors.lastname: van Leeuwen
authors.forename: S J
authors.initials: SJ
authors.lastname: Hurwitz
authors.forename: M
authors.initials: M
authors.lastname: Selig
authors.forename: G R
authors.initials: GR
authors.lastname: Dickersin
authors.forename: A
authors.initials: A
authors.lastname: Flint
authors.forename: H R
authors.initials: HR
authors.lastname: Byers
authors.forename: L B
authors.initials: LB
authors.lastname: Chen
mesh_terms: D002614:Chelating Agents / Q000494:pharmacology*; D007464:Clioquinol / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009187:Myelitis / Q000209:etiology; D009902:Optic Neuritis / Q000209:etiology; D013577:Syndrome; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000494:pharmacology*
chemical_list: D002614:Chelating Agents; D007464:Clioquinol; D015032:Zinc