Effect of 5‐Chloro‐7‐iodo‐8‐hydroxy‐quinoline (Clioquinol) on the Uptake and Distribution of Nickel, Zinc and Mercury in Mice

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Abstract
5‐Chloro‐7‐iodo‐8‐hydroxy‐quinoline (clioquinol) was found to induce a very marked increase in the concentration of 63Ni2+ in various tissues of mice when given orally together with the metal, compared with oral administrations of 63Ni2+ only. Markedly increased tissue concentrations, although less expressed than for the 63Ni2+, were also observed for 65Zn2+. Clioquinol increased the tissue levels of 203Hg2+ to a lesser extent. When clioquinol was given intraperitoneally and 63Ni2+ was given intravenously there were also very markedly increased tissue levels of the metal, compared with intravenous injections of 63Ni2+ only. It was also shown that the urinary excretion of 63Ni2+ was greatly increased in mice given the metal orally together with clioquinol, compared with mice given the 63Ni2+ only. Clioquinol and other 8‐hydroxy‐quinolines form lipophilic chelates with metallic cations and the observed effects on the tissue‐disposition of the metals are probably due to a facilitated penetration through the cellular membranes. Determinations of the chloroform:water partition coefficients showed the highest lipophilicity for the nickel‐clioquinol‐complex followed in decreasing order by the complexes with zinc and mercury. These data suggest that the ability of the clioquinol to affect the uptake of the metals in the cells may be related to the relative lipophilicity of the metal‐clioquinol‐complexes. Clioquinol and other halogenated 8‐hydroxy‐quinolines are linked with the SMON‐syndrom, which has been observed preferentially in Japan. It is suggested that the pathogenesis of SMON may involve an accumulation of toxic concentrations of metals in the tissues due to facilitated uptake by complex‐formation with halogenated 8‐hydroxy‐quinolines. The Japanese have been more heavily exposed to metals by environmental pollution than most people in other countries, explaining the prevalent occurrence of SMON in Japan.