Chlorate poisoning: mechanism of toxicity.
Intoxications with chlorate salts are characterized by methaemoglobin formation, haemolysis and renal insufficiency. The toxic effects on the erythrocyte can be reproduced in vitro. Incubation of human and rabbit erythrocytes with chlorates induces a concentration-dependent oxidation of haemoglobin. This methaemoglobin formation is followed by denaturation of the globin, a cross-linking of erythrocyte membrane proteins and an inactivation of membrane enzymes. The high sensitivity of glucose-6-phosphate dehydrogenase to denaturation by chlorate explains the inefficacy of methylene blue to reduce methaemoglobin formed, as the antidotal effect of methylene blue depends on NADPH formed mainly by the oxidation of glucose-6-phosphate. The observed changes occur only in the presence of methaemoglobin which forms a destabilising complex with chlorate. Methaemoglobin thus autocatalytically increases methaemoglobin formation and destruction of the erythrocyte. As the rabbit is known to have a high methaemoglobin-reduction capacity, human and rabbit erythrocytes were compared. In vitro, the rabbit erythrocyte is less sensitive to oxidative attack than the human red cell. In vivo, an oral dose of sodium chlorate (1 g/kg body wt.) resulted in high serum (16 +/- 4 mM) and urine concentrations (246 +/- 99 mM) in the rabbit. Methaemoglobin was not formed nor could a nephrotoxic effect be observed. These experiments also indicate that the nephrotoxicity of chlorate is mediated by methaemoglobin catalysis.
Steffen
C
C
Federal Health Office, Institut für Arzneimittel, Germany.
Wetzel
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E
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D002704:Chlorates / Q000633:toxicity*; D004591:Electrophoresis, Polyacrylamide Gel; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D008706:Methemoglobin / Q000096:biosynthesis; D011817:Rabbits; D013045:Species Specificity
D002704:Chlorates; D000255:Adenosine Triphosphate; D008706:Methemoglobin; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase