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Atractyloside

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Daniel J. Müller – One of the best experts on this subject based on the ideXlab platform.

  • Probing the interactions of carboxy-Atractyloside and Atractyloside with the yeast mitochondrial ADP/ATP carrier.
    Structure (London England : 1993), 2010
    Co-Authors: Alexej Kedrov, Alex M. Hellawell, Adam Klosin, R. Bill Broadhurst, Edmund R. S. Kunji, Daniel J. Müller

    Abstract:

    Summary Mitochondrial ADP/ATP carriers are inhibited by two natural compounds, Atractyloside (ATR) or carboxy-Atractyloside (CATR), which differ by one carboxylate group. The interactions of the inhibitors with the carrier were investigated by single-molecule force spectroscopy. Transmembrane α helices of the ATR-inhibited carrier displayed heterogeneous mechanical and kinetic properties. Whereas α helix H2 showed the most brittle mechanical properties and lowest kinetic stability, α helix H5 was mechanically the most flexible and possessed a kinetic stability 9 orders of magnitude greater than that of α helix H2. In contrast, CATR-binding substantially increased the kinetic stability of α helix H2 and tuned the mechanical flexibility of α helices H5 and H6. NMR spectroscopy confirmed that the additional carboxylate group of CATR binds to the sixth α helix, indicating that the enhanced stability of H2 is mediated via interactions between CATR and H6.

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  • probing the interactions of carboxy Atractyloside and Atractyloside with the yeast mitochondrial adp atp carrier
    Structure, 2010
    Co-Authors: Alexej Kedrov, Daniel J. Müller, Alex M. Hellawell, Adam Klosin, Edmund R. S. Kunji, Bill R Broadhurst

    Abstract:

    Summary Mitochondrial ADP/ATP carriers are inhibited by two natural compounds, Atractyloside (ATR) or carboxy-Atractyloside (CATR), which differ by one carboxylate group. The interactions of the inhibitors with the carrier were investigated by single-molecule force spectroscopy. Transmembrane α helices of the ATR-inhibited carrier displayed heterogeneous mechanical and kinetic properties. Whereas α helix H2 showed the most brittle mechanical properties and lowest kinetic stability, α helix H5 was mechanically the most flexible and possessed a kinetic stability 9 orders of magnitude greater than that of α helix H2. In contrast, CATR-binding substantially increased the kinetic stability of α helix H2 and tuned the mechanical flexibility of α helices H5 and H6. NMR spectroscopy confirmed that the additional carboxylate group of CATR binds to the sixth α helix, indicating that the enhanced stability of H2 is mediated via interactions between CATR and H6.

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Peter H. Bach – One of the best experts on this subject based on the ideXlab platform.

  • Adenine nucleotide and calpain inhibitor I protect against Atractyloside-induced toxicity in rat renal cortical slices in vitro.
    Archives of toxicology, 2001
    Co-Authors: David K. Obatomi, Richard Blackburn, Peter H. Bach

    Abstract:

    Atractyloside is a compound with a documented nephrotoxicity. It induces renal tubular necrosis at high doses and apoptosis at lower doses. This study investigates the potential protective effect of some chemical agents against Atractyloside-induced nephrotoxicity in vitro using the precision-cut rat renal cortical slices obtained from kidneys of Wistar rats. For co-incubation experiments, slices were incubated for 3 h at 37°C on a rocker platform with various chemical agents: ADP (5 mM), calpain inhibitor I (CPI, 1 mM), stevioside (STV, 2.5 mM) or probenecid (PRB, 2.5 mM) in the presence or absence of Atractyloside (2 mM). For pre-incubation experiments, slices were incubated with the same chemical agents for 1 h before exposure to Atractyloside. The nephrotoxic effects of Atractyloside (2 mM) alone were manifested in several ways: by a marked increase in lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) leakage, significant inhibition of p-aminohippurate (PAH) accumulation, marked depletion of intracellular ATP and reduced glutathione (GSH), and a significant reduction in pyruvate-stimulated gluconeogenesis. Co-incubation of slices with ADP or CPI and Atractyloside completely blocked Atractyloside-induced increase in LDH leakage, but not ALP leakage. Atractyloside-induced depletion of ATP and reduced gluconeogenesis was prevented by co-incubation with ADP or CPI. Furthermore, co-incubation of slices with STV and Atractyloside, but not PRB, completely abolished Atractyloside-induced depletion of ATP and decreased gluconeogenesis in the slices. Pre-incubation of slices with either ADP or CPI protected against Atractyloside-induced increase in LDH leakage, reduced ATP and decreased gluconeogenesis. PAH uptake in the slices was inhibited by Atractyloside and PRB in a time-dependent manner. While ADP and CPI were found to exert complete protection against Atractyloside-induced toxicity irrespective of treatment schedule, STV is effective only under certain conditions, and PRB offer no protection at all. The results of this study demonstrate the usefulness of renal cortical slices as toxicology tool for evaluating and screening compounds for their potential protective effects, and are supportive of a role of adeninine nucleotide (ADP) and protease inhibitor (CPI) in protecting against Atractyloside-induced cell injury.

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  • The toxic mechanism and metabolic effects of Atractyloside in precision-cut pig kidney and liver slices
    Archives of toxicology, 1998
    Co-Authors: David K. Obatomi, Nguyen T. K. Thanh, Stephen Brant, Peter H. Bach

    Abstract:

    The toxic and cellular metabolic eAects of at- ractyloside, a diterpenoid glycoside, which causes fatal renal and hepatic necrosis in vivo in animals and hu- mans, have been investigated in tissue slices prepared from male domestic pig kidney and liver. Precision-cut slices (200 lm thick) were incubated with Atractyloside at concentrations of 200 lM, 500 lM, 1.0 mM and 2.0 mM for 3 h at 37 ∞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 as- sessed. 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. At- ractyloside at concentrations of ‡200 lM caused a sig- nificant increase in lipid peroxidation, but only in liver slices. However, Atractyloside at concentrations of ‡200 lM 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 aAected by Atractyloside in both kidney and liver slices. Renal and hepatic pyruvate-stimulated gluconeogenesis were significantly (P < 0.05) inhibited at Atractyloside concentrations of ‡500 lM. Accumulation of organic anion p-amino- hippuric acid (PAH) was also inhibited in renal cortical slices at Atractyloside concentrations of ‡500 lM. These results suggest that the observable in vivo eAect of at- ractyloside can be reproduced in slices and that basic mechanistic diAerences exist in the mode of toxicity in liver and kidney tissues. The data also raise the possi- bility 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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David K. Obatomi – One of the best experts on this subject based on the ideXlab platform.

  • Adenine nucleotide and calpain inhibitor I protect against Atractyloside-induced toxicity in rat renal cortical slices in vitro.
    Archives of toxicology, 2001
    Co-Authors: David K. Obatomi, Richard Blackburn, Peter H. Bach

    Abstract:

    Atractyloside is a compound with a documented nephrotoxicity. It induces renal tubular necrosis at high doses and apoptosis at lower doses. This study investigates the potential protective effect of some chemical agents against Atractyloside-induced nephrotoxicity in vitro using the precision-cut rat renal cortical slices obtained from kidneys of Wistar rats. For co-incubation experiments, slices were incubated for 3 h at 37°C on a rocker platform with various chemical agents: ADP (5 mM), calpain inhibitor I (CPI, 1 mM), stevioside (STV, 2.5 mM) or probenecid (PRB, 2.5 mM) in the presence or absence of Atractyloside (2 mM). For pre-incubation experiments, slices were incubated with the same chemical agents for 1 h before exposure to Atractyloside. The nephrotoxic effects of Atractyloside (2 mM) alone were manifested in several ways: by a marked increase in lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) leakage, significant inhibition of p-aminohippurate (PAH) accumulation, marked depletion of intracellular ATP and reduced glutathione (GSH), and a significant reduction in pyruvate-stimulated gluconeogenesis. Co-incubation of slices with ADP or CPI and Atractyloside completely blocked Atractyloside-induced increase in LDH leakage, but not ALP leakage. Atractyloside-induced depletion of ATP and reduced gluconeogenesis was prevented by co-incubation with ADP or CPI. Furthermore, co-incubation of slices with STV and Atractyloside, but not PRB, completely abolished Atractyloside-induced depletion of ATP and decreased gluconeogenesis in the slices. Pre-incubation of slices with either ADP or CPI protected against Atractyloside-induced increase in LDH leakage, reduced ATP and decreased gluconeogenesis. PAH uptake in the slices was inhibited by Atractyloside and PRB in a time-dependent manner. While ADP and CPI were found to exert complete protection against Atractyloside-induced toxicity irrespective of treatment schedule, STV is effective only under certain conditions, and PRB offer no protection at all. The results of this study demonstrate the usefulness of renal cortical slices as toxicology tool for evaluating and screening compounds for their potential protective effects, and are supportive of a role of adeninine nucleotide (ADP) and protease inhibitor (CPI) in protecting against Atractyloside-induced cell injury.

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  • The toxic mechanism and metabolic effects of Atractyloside in precision-cut pig kidney and liver slices
    Archives of toxicology, 1998
    Co-Authors: David K. Obatomi, Nguyen T. K. Thanh, Stephen Brant, Peter H. Bach

    Abstract:

    The toxic and cellular metabolic eAects of at- ractyloside, a diterpenoid glycoside, which causes fatal renal and hepatic necrosis in vivo in animals and hu- mans, have been investigated in tissue slices prepared from male domestic pig kidney and liver. Precision-cut slices (200 lm thick) were incubated with Atractyloside at concentrations of 200 lM, 500 lM, 1.0 mM and 2.0 mM for 3 h at 37 ∞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 as- sessed. 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. At- ractyloside at concentrations of ‡200 lM caused a sig- nificant increase in lipid peroxidation, but only in liver slices. However, Atractyloside at concentrations of ‡200 lM 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 aAected by Atractyloside in both kidney and liver slices. Renal and hepatic pyruvate-stimulated gluconeogenesis were significantly (P < 0.05) inhibited at Atractyloside concentrations of ‡500 lM. Accumulation of organic anion p-amino- hippuric acid (PAH) was also inhibited in renal cortical slices at Atractyloside concentrations of ‡500 lM. These results suggest that the observable in vivo eAect of at- ractyloside can be reproduced in slices and that basic mechanistic diAerences exist in the mode of toxicity in liver and kidney tissues. The data also raise the possi- bility 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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