Nephrotoxicity of paracetamol in the rat--mechanistic and therapeutic aspects

Besides hepatotoxicity, paracetamol may exert nephrotoxic effects in experimental animals and patients. The present study in rats shows that antidotes known to protect against hepatotoxicity, such as methionine or N-acetylcysteine, are not effective in preventing paracetamol-induced kidney damage. Only diethyldithiocarbamate, an inhibitor of microsomal monooxygenases, provided complete protection against both hepato- and nephrotoxicity. While a marked depletion of glutathione was observed in the liver, no such effect was seen in the kidney. These data suggest that the mechanism of paracetamol nephrotoxicity seems to be quite different from that responsible for the hepatotoxicity. The hypothesis that a C-S-lyase-mediated final metabolism of paracetamol-S conjugates in the kidney might be responsible for nephrotoxicity needs support by further experimental investigations.