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Publication Detail
The toxic mechanism and metabolic effects of atractyloside in precision-cut pig kidney and liver slices
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Obatomi DK, Thanh NTK, Brant S, Bach PH
  • Publication date:
    1998
  • Pagination:
    {524-530}
  • Journal:
    ARCHIVES OF TOXICOLOGY
  • Volume:
    72
  • Article number:
    8
  • Print ISSN:
    0340-5761
  • Notes:
    unique-id: ISI:000075930500009
Abstract
The toxic and cellular metabolic effects of atractyloside, a diterpenoid glycoside, which causes fatal renal and hepatic necrosis in vivo in animals and humans, have been investigated in tissue slices prepared from male domestic pig kidney and liver. Precision-cut slices (200 mu m thick) were incubated with atractyloside at concentrations of 300 mu M, 500 mu M, 1.0 mM and 2.0 mM for 3 h at 37 degrees C and changes in lipid profile and pyruvate-stimulated gluconeogenesis investigated. Lipid peroxidative changes, reduced glutathione (GSH) and ATP content, the release of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), alanine and aspartate aminotransferase (ALT/AST) were also assessed. After 3 h of incubation, atractyloside caused a significant (P < 0.01) and concentration-dependent leakage of LDH and ALP from kidney slices. Only LDH leakage was significantly elevated in liver slices while ALT and AST leakage showed marginal increase. Atractyloside at concentrations of greater than or equal to 200 mu M caused a significant increase in lipid peroxidation, bur only in liver slices. However, atractyloside at concentrations of greater than or equal to 200 mu M caused a marked depletion of GSH and ATP content in both kidney and liver slices. There was a marked decrease in total and individual phospholipid in kidney but not in liver slices. However, cholesterol and triacylglycerol levels were not affected by atractyloside in both kidney and liver slices. Renal and hepatic pyruvate-stimulated gluconeogenesis were significantly (P < 0.05) inhibited at atractyloside concentrations of greater than or equal to 500 mu M. Accumulation of organic anion p-amino-hippuric acid (PAH) was also inhibited in renal cortical slices at atractyloside concentrations of greater than or equal to 500 mu M. These results suggest that the observable in vivo effect of atractyloside call be reproduced in slices and that basic mechanistic differences exist in the mode of toxicity in liver and kidney tissues. The data also raise the possibility that the mechanistic basis of metabolic alterations in these tissues following treatment with atractyloside may be relevant to target selective toxicity.
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