Neurotoxicology
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The mechanism(s) and site(s) of the neurotoxic effect of cisplatin (CDDP) are still not entirely elucidated. A more detailed knowledge of these aspects of CDDP treatment might be useful to obtain a better understanding of the pathogenesis of its peripheral neurotoxicity, which is the dose-limiting side effect of CDDP. In the present study, the occurrence of CDDP-induced DNA-platination in dorsal root ganglia (DRG) of rats was evaluated in relation to DRG neuron pathological changes and CDDP-induced neuronopathy. ⋯ Nuclear immunostaining for Pt-DNA adducts was observed in tubular cells of the kidney in 75% of the evaluated CDDP-treated rats, while in DRG cells CDDP-induced Pt-DNA adducts formation was found in 43% of the evaluated CDDP-treated rats. CDDP-induced DNA-platination was demonstrated in rat DRG neurons using a schedule of chronic CDDP administration which induced the onset of a sensory neuronopathy with secondary peripheral neuropathy. This finding further supports the hypothesis that CDDP is neurotoxic because it directly damages the DRG neurons.
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Treatment of metastatic tumors with ionic platinum compounds is hampered by the potent nephrotoxic, ototoxic and neurotoxic properties of these drugs. Recent studies have shown that sulfur-containing antioxidants relieve the dose limiting side effects of cis-diamminedichloroplatinum (CDDP), the most commonly used ionic platinum therapy. Here we report that both isomers of the sulfur-containing antioxidant methionine (MET) completely block the in vivo ototoxic and nephrotoxic effects of CDDP, and the duration of MET otoprotection is longer than has been previously reported. ⋯ Mortality among CDDP-treated subjects increased steadily over the period of the study, while all of the MET-protected rats survived. Finally, the efficacy of CDDP in the presence of L- or D-MET was evaluated in vitro using cultures of MTLN-3 breast tumor cell lines, and in vivo using implanted MTLN-3 tumors. Both L- and D-MET reduced the ability of CDDP to kill tumor cells in vitro and in vivo, however, our data suggest that a higher proportion of the antineoplastic activity of CDDP is retained in the presence of L- MET.
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The hyperintense signal in the globus pallidus of cirrhotic patients on T1-weighted magnetic resonance (MR) imaging has been postulated to arise from deposition of paramagnetic manganese2+ (Mn). Intestinal absorption of both iron and Mn are increased in iron deficiency; iron deficiency may therefore increase susceptibility to Mn neurotoxicity. To investigate the relationships between MR signal abnormalities and Mn and Fe status, 21 patients with chronic liver disease were enrolled (alcoholic liver disease, 5; primary biliary cirrhosis, 9; primary sclerosing cholangitis, 3; hepatitis B virus, 2; hepatitis C virus, 1; alpha1-antitrypsin deficiency, 1). ⋯ These findings confirm the association of Mn with the development of pallidal hyperintensity in patients with liver disease. We further found that iron deficiency is an exacerbating factor, probably because of increased intestinal absorption of Mn. We therefore recommend that patients with chronic liver disease avoid Mn supplements without concurrent iron supplementation.
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Methylcyclopentadienyl Manganese Tricarbonyl (MMT) has been used since the 1970s in the U. S. as a gasoline octane enhancer Extensive testing of the effects of MMT on regulated gaseous emissions carried out on a wide variety of automobiles showed that use of MMT resulted in significantly lower NOx emissions Tests showed that less than 15% of the manganese from MMT combustion was emitted from the tailpipe, mostly in the PM2.5 fraction as manganese phosphate, with some manganese sulfate and a very small amount of manganese oxide. MMT has been used in Canada in virtually all unleaded gasoline for about 20 years. ⋯ Exposures to manganese among the general population in Toronto are well within safe limits determined by the U. S. EPA and other standard setting bodies around the world.
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In 1994, the U. S. Environmental Protection Agency (EPA) denied a petition by Ethyl Corporation to allow the use of methylcyclopentadienyl manganese tricarbonyl (MMT) in unleaded gasoline, because of health concerns related to the inhalation of manganese (Mn) particulate emissions from combusted MMT. ⋯ To improve the risk characterization, better information on Mn/MMT population exposures and health effects is needed. Much of this information is expected to be obtained under provisions of Section 211 of the Clean Air Act. Among the specific issues that remain to be resolved are the form or forms of Mn emitted from the combustion of MMT in gasoline and the potentially different toxic properties of Mn in different forms.