Species differences in the hepatotoxicity of paracetamol are due to differences in the rate of conversion to its cytotoxic metabolite.

The cytotoxicity of paracetamol and of its putative toxic metabolite, N-acetyl-p-benzo-quinoneimine (NABQI) have been investigated in hepatocytes from hamster, mouse, rat and human liver. Whereas paracetamol readily caused cell blebbing and a loss of viability in hepatocytes from mouse and hamster, human and rat hepatocytes were much more resistant to these effects. In marked contrast, there were no significant differences in the sensitivity of the cells from any species to the toxic effects of NABQI. Glutathione depletion by NABQI and paracetamol correlated very well with the toxic effects of these compounds. It is concluded that species differences in sensitivity to the hepatotoxicity of paracetamol are due almost entirely to differences in the rate of formation of NABQI, and not to any intrinsic differences in sensitivity or in any difference in the fate of NABQI once formed. Further, man appears to be relatively resistant to the hepatotoxic effects of paracetamol, and the results in hepatocytes were confirmed by both in vitro and in vivo analyses.