EFFECT OF AGENTS WHICH MODIFY RETICULOENDOTHELIAL SYSTEM FUNCTION ON ACUTE PHALLOIDIN-INDUCED LETHALITY AND HEPATOTOXICITY IN MICE

The relationship between reticuloendothelial system (RES) function and acute phalloidin intoxication was studied in mice. Pretreatment with compounds that stimulate (zymosan) or depress (methyl palmitate and praseodymium nitrate, Pr(NO3)(3)) the RES resulted in protection against phalloidin-induced lethality and hepatotoxicity, as assessed by morphological analysis. However, triolein (which stimulates the RES) was ineffective against phalloidin. The timing of pretreatment with the effective compounds showed a correlation between modified in vivo RES function (phagocytosis) and protection against the toxin. The effects of pretreatment with zymosan and Pr(NO3)(3) were further characterized. Hepatic damage induced by phalloidin was significantly decreased by these agents, as judged by morphological analysis as well as by serum aspartate aminotransferase and alanine aminotransferase release. This study also showed that there was no correlation between the capacity of Kupffer cells to produce nitrite and prophylaxis against phalloidin. However, liver cell proliferation was increased by zymosan and Pr(NO3)(3) in parallel with protection against the toxin. Furthermore, freshly isolated hepatocytes from zymosan- or Pr(NO3)(3)-treated mice were less sensitive to phalloidin in vitro. These results indicate that the protective effect of these agents against phalloidin-induced hepatotoxicity may be mediated by their mitogenic properties. (C) 1995 Academic Press, Inc.