Na+/K(+)-ATPase in rat brain and erythrocytes as a possible target and marker, respectively, for neurotoxicity: studies with chlordecone, organotins and mercury compounds.
Due to the inaccessibility of human nerve tissue for direct biochemical evaluation, there appears to be a need to identify peripheral markers which will reflect toxicity to the central nervous system by relatively non-invasive means. The aim of this study was to investigate whether the enzyme Na+/K(+)-ATPase in erythrocytes could be used as a marker for effects on the same enzyme in brain tissue. The compounds chosen to test this hypothesis were the pesticide chlordecone, the organotin compounds triethyltin and tributyltin, mercuric chloride and methyl mercury. All compounds were found to inhibit in vitro Na+/K(+)-ATPase activity in rat brain (IC50s = 0.9-56 microM) and in rat erythrocytes (IC50s = 1.2-66 microM) with similar potencies. However, administration of these compounds in vivo at high doses produced no significant inhibition of either brain or erythrocyte Na+/K(+)-ATPase activity, despite observed symptoms of neurotoxicity. Dialysis experiments indicated that dissociation of the compounds by dilution during tissue preparation was not responsible for the lack of detectable in vivo inhibition. Measurements of metal concentrations in brain by atomic absorption spectrometry after in vivo administration of triethyltin, mercuric chloride and methyl mercury indicated that levels of these compounds were too low to inhibit significantly NA+/K(+)-ATPase activity. These results suggest that inhibition of Na+/K(+)-ATPase activity might not represent the mechanism responsible for the neurotoxicity of these compounds, and that erythrocyte Na+/K(+)-ATPase activity is not a useful marker for neurotoxicity following acute exposures.
Maier
W E
WE
Department of Environmental Health, University of Washington, Seattle 98195.
Costa
L G
LG
D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D007631:Chlordecone / Q000008:administration & dosage / Q000633:toxicity*; D003956:Dialysis; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology*; D066298:In Vitro Techniques; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D008627:Mercuric Chloride / Q000008:administration & dosage / Q000633:toxicity*; D008767:Methylmercury Compounds / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D014220:Trialkyltin Compounds / Q000008:administration & dosage / Q000633:toxicity*; D014267:Triethyltin Compounds / Q000008:administration & dosage / Q000633:toxicity*
D015415:Biomarkers; D007306:Insecticides; D008767:Methylmercury Compounds; D014220:Trialkyltin Compounds; D014267:Triethyltin Compounds; C011559:tributyltin; D008627:Mercuric Chloride; C031575:triethyltin; D000254:Sodium-Potassium-Exchanging ATPase; D007631:Chlordecone