TOXICITY OF ATRACTYLOSIDE IN PRECISION-CUT RAT AND PORCINE RENAL AND HEPATIC TISSUE-SLICES

Atractyloside (ATR) causes acute fatal renal and hepatic necrosis in a nimals and humans. Precision-cut renal cortical and hepatic slices (20 0 +/- 15 mu m) from adult male Wistar rat and domestic pigs, incubated with ATR (0.2-2.0 mM) for 3 h at 37 degrees C, inhibited pyruvate-sti mulated gluconeogenesis in a concentration and time-dependent manner. p-Aminohippurate accumulation was significantly inhibited in both rat and pig renal cortical slices from 0.2 mM ATR (p < 0.05). There was a small decrease in mitochondrial reduction of 3-(4,5-dimethylthiazol-2- yl)-2,5 -diphenyltetrazolium to formazan in both rat and pig kidney sl ices, which was significant at greater than or equal to 2 mM, but no c hanges in liver slices from either species. However, cellular ATP was significantly depleted at greater than or equal to 0.2 mM ATR in kidne y and in liver slices from both species, ATR also caused a marked leak age of lactate dehydrogenase and alkaline phosphatase from both pig an d rat kidney slices at all concentrations, but only lactate dehydrogen ase was significantly elevated in liver slices from both species. ATR greater than or equal to 0.5 mM caused a significant increase in lipid peroxidation, but only in liver slices of both species, and greater t han or equal to 0.2 mM ATR caused a marked depletion of reduced glutat hione and significant increase in oxidized glutathione in both kidney and liver slices of both species. However, GSH to GSSG ratio was only significantly altered in the liver slices, indicating that oxidative s tress may be the cause of toxicity in this organ. Both rat and pig tis sue slices from the same organ responded similarly to ATR, although th eir basal biochemistry was different. ATR toxicity to both kidney and liver showed similar patterns but it appears that the mechanisms of to xicity are different. While cytotoxicity of ATR in kidney is only acco mpanied with GSH depletion, that of the liver is linked to both lipid peroxidation and GSH depletion. Striated muscle slices from both speci es were not affected by the highest ATR concentration. This further st rengthens the argument that the molecular basis of ATR, target selecti ve toxicity, is not a measure of the interaction between ATR and mitoc hondria and that other factors such as selective uptake are involved. Precision-cut tissue slices show organ-specific toxicity in kidney and liver from both rat and pig and suggest different mechanisms of injur y for each organ. (C) 1998 Academic Press.