TOXICITY OF AZATHIOPRINE AND MONOCROTALINE IN MURINE SINUSOIDAL ENDOTHELIAL-CELLS AND HEPATOCYTES - THE ROLE OF GLUTATHIONE AND RELEVANCE TO HEPATIC VENOOCCLUSIVE DISEASE

The mechanisms leading to hepatic venoocclusive disease (HVOD) remain largely unknown, Azathioprine and monocrotaline were studied as part o f a series of studies looking at a variety of toxins that induce HVOD to find common features that might be of pathogenic significance. In a previous study, dacarbazine showed selective in vitro toxicity to sin usoidal endothelial cells (SEC) compared with hepatocytes and a key ro le for SEC glutathione (GSH) was demonstrated. Murine SEC and hepatocy tes were isolated and Studied in culture. Azathioprine and monocrotali ne were found to be selectively more toxic to SEC than to hepatocytes, The relative resistance of hepatocytes to azathioprine was due to enh anced GSH defense: hepatocytes exposed to azathioprine maintained intr acellular GSH levels better than SEC, particularly when supplemental G SH precursors were added, and hepatocyte resistance was completely ove rcome by depletion of intracellular GSH. In contrast, monocrotaline to xicity in hepatocytes was largely unaffected by depletion of GSH, whic h suggests that selectivity of monocrotaline for SEC may be attributab le to differences in metabolic activation, Both compounds are detoxifi ed by GSH in SEC, as demonstrated by enhanced toxicity in the presence of buthionine sulfoximine (BSO) and attenuation of toxicity with exog enous GSH. SEC GSH levels were more than 70% to 80% depleted by monocr otaline and azathioprine, respectively, before cell death. Azathioprin e and monocrotaline are selectively toxic to SEC; the mechanism of tox icity in the SEC may be caused by profound GSH depletion.