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Clioquinol (5-chloro-7-indo-8-quinolinol), a chelator and ionophore of copper/zinc, was extensively used as an amebicide to treat indigestion and diarrhea in the mid-1900s. However, it was withdrawn from the market in Japan because its use was epidemiologically linked to an increase in the incidence of subacute myelo-optic neuropathy (SMON). SMON is characterized by the subacute onset of sensory and motor disturbances in the lower extremities with occasional visual impairments, which are preceded by abdominal symptoms. Although pathological studies demonstrated axonopathy of the spinal cord and optic nerves, the underlying mechanisms of clioquinol toxicity have not been elucidated in detail. In the present study, a reporter assay revealed that clioquinol (20–50 µM) activated metal response element-dependent transcription in human neuroblastoma SH-SY5Y cells. Clioquinol significantly increased the cellular level of zinc within 1 h, suggesting zinc influx due to its ionophore effects. On the other hand, clioquinol (20–50 µM) significantly increased the cellular level of copper within 24 h. Clioquinol (50 µM) induced the oxidation of the copper chaperone antioxidant 1 (ATOX1), suggesting its inactivation and inhibition of copper transport. The secretion of dopamine-β-hydroxylase (DBH) and lysyl oxidase, both of which are copper-dependent enzymes, was altered by clioquinol (20–50 µM). Noradrenaline levels were reduced by clioquinol (20–50 µM). Disruption of the ATOX1 gene suppressed the secretion of DBH. This study suggested that the disturbance of cellular copper transport by the inactivation of ATOX1 is one of the mechanisms involved in clioquinol-induced neurotoxicity in SMON. [ABSTRACT FROM AUTHOR]

Abstract: To carry out a primary risk assessment in the Inland Sea of Japan for 2,2′-dipyridyldisulfide [(PS)2], a metal pyrithione photodegradation product, we used a methodology based on the species sensitivity distribution (SSD) estimated with a Bayesian statistical model. We first conducted growth inhibition tests with three marine phytoplankton species, Tetraselmis tetrathele, Chaetoceros calcitrans, and Dunaliella tertiolecta. We also performed acute and early life stage toxicity (ELS) tests with a teleost fish, the mummichog (Fundulus heteroclitus). The algal growth inhibition tests revealed that the 72-h EC50 ranged from 62 to 1100μg/L. Acute toxicity tests with larval mummichogs revealed that the 96-h LC50 was approximately 500μg/L based on the actual toxicant concentrations. ELS testing of (PS)2 under continuous flow-through conditions for 50 days revealed that growth was the most sensitive endpoint, and both total length and body weight were significantly lower in the groups exposed to 27μg/L (PS)2 compared to the solvent control group. We determined a lowest observed effect concentration of 17μg/L and a NOEC of 5.9μg/L based on the actual toxicant concentrations. By using the ecotoxicity data (LC50 and EC50) from this study and previous work, we calculated a hazardous concentration that should protect 95% and 99% of species (HC5 and HC1) based on the SSD derived with a Bayesian statistical model. The medians with 90% confidence intervals (parentheses) of the HC5 and HC1 were 31.0 (3.2, 101.8)μg/L and 10.1 (0.5, 44.2)μg/L, respectively. In the ELS test, about 80% of hatched larvae exposed to 243-μg/L (PS)2 displayed a notochord undulation. To elucidate the cause of the notochord undulation, we carried out embryo toxicity tests by exposing embryos at various developmental stages to (PS)2. Exposure to (PS)2 through the entire gastrulae stage was important to induction of the morphological abnormality. Lysyl oxidase activity was significantly decreased in these embryos compared to the control group, a suggestion that lysyl oxidase-mediated collagen fiber organization, which is essential for notochord formation, is disrupted because of (PS)2 toxicity. We also investigated the occurrence of (PS)2 in water from several coastal sites of the Inland Sea and detected (PS)2 at concentrations of <0.1–0.4ng/L. Comparison of environmental concentrations to the HC values suggests that the current ecological risk posed by (PS)2 in the Inland Sea is low. This is the first report of the detection of a metal pyrithione degradation product in the natural marine environment. [Copyright &y& Elsevier]