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PubMed1986

Stevioside, the sweet glycoside of Stevia rebaudiana, inhibits the action of atractyloside in the isolated perfused rat liver.

Stevioside inhibits the action of atractyloside on energy metabolism in the isolated perfused rat liver. The effects of atractyloside on glycolysis, glycogenolysis, gluconeogenesis and oxygen uptake are decreased by stevioside. The concentration for half-maximal action is 0.5 mM. The site of the action is located on the outside of the cell. Possibly, stevioside affects the transport of atractyloside across the cell membrane.

Animals↗
PubMed1970

35S-Atractyloside binding affinity to the inner mitochondrial membrane.

Isolated inner mitochondrial membrane contains a small number of binding sites for atractyloside (of the order of 0.1 nmole/mg of protein) with very high binding affinity (half saturation at 0.014 &mgr;M atractyloside). The high affinity binding ability of the inner mitochondrial membrane is markedly decreased upon aging, acidification of the medium or addition of ADP, but remains unchanged in the presence of uncouplers such as FCCP. Added ADP causes a two-step transition from the high affinity binding to low affinity binding (K(d) > 0.50 &mgr;M) and concomitantly a significant increase of the measured number of binding sites (about a doubling). The half maximum effect in the first step transition is given by 1 &mgr;M ADP. The use of 35S-atractyloside as a probe of the inner mitochondrial membrane conformation specifically related to the adenine nucleotide translocation is discussed.

Journal Article↗
PubMed1986

6'-O-dansyl-gamma-aminobutyryl atractyloside, a fluorescent probe of the ADP/ATP carrier: exploration of conformational changes of the membrane-bound ADP/ATP carrier elicited by substrates and inhibitors.

A fluorescent atractyloside analogue, the 6'-O-dansyl-gamma-aminobutyryl atractyloside (DGA), has been used to probe the binding of the inhibitors carboxyatractyloside (CATR) and bongkrekic acid (BA) and nucleotide substrates to the membrane-bound ADP/ATP carrier protein in beef heart mitochondria. Binding and release of DGA were followed by fluorescence responses. Specifically bound DGA was fully released by CATR alone, or by BA in the presence of micromolar amounts of ADP. In the absence of the inhibitors, ADP increased the rate of the specific binding of DGA. The effect of ADP was shared by transportable nucleotides. Non transportable nucleotides were ineffective. These data are consistent with the previously described CATR and BA conformations of the ADP/ATP carrier that are able to bind CATR and BA respectively, the transition between the two conformations being accelerated by micromolar concentrations of transportable nucleotides.

Animals↗
PubMed1991

The isolation of a storage organelle of atractyloside in Callilepis laureola.

A method has been developed for the preparation of protoplasts from both the leaves and tubers of Callilepis laureola, a plant used extensively as a medicament by black people in South Africa. The cellular vacuoles from these protoplasts were isolated and tested for the presence of the nephrotoxic substance, atractyloside, by thin layer chromatography and immunoassay. Both methods indicate that the vacuole of C. laureola is the primary site of storage for atractyloside in the cells of the tuber.

Atractyloside↗
PubMed2006

Atractyloside and 5-hydroxydecanoate block the protective effect of puerarin in isolated rat heart.

The aim of the present study was to determine whether the clinically effective cardioprotection conferred by puerarin (Pue) against ischemia and reperfusion is mediated by mitochondrial transmembrane pores and/or channels. Hearts isolated from male Sprague-Dawley rats were perfused on a Langendorff apparatus and subjected to 30 min of global ischemia followed by 120 min of reperfusion. The production of formazan, which provides an index of myocardial viability, was measured by absorbance at 550 nm, and the level of lactate dehydrogenase (LDH) in the coronary effluent was determined. In this model, Pue (0.0024-2.4 mmol/l) had a dose-dependent, negatively inotropic effect. Pretreatment with Pue at 0.24 mmol/l for 5 min before ischemia increased myocardial formazan content, reduced LDH release, improved recovery of left ventricular end-diastolic pressure and rate-pressure product (left ventricular developed pressure multiplied by heart rate) during reperfusion. Administration of atractyloside (20 micromol/l), an opener of the mitochondrial permeability transition pore, for the first 20 min of reperfusion, and 5-hydroxydecanoate (100 micromol/l), the mitochondrial-specific ATP-sensitive potassium channel blocker, for 20 min before ischemia, attenuated the protective effects of Pue. In mitochondria isolated from hearts pretreated with 0.24 mmol/l Pue for 5 min, a significant inhibition of Ca(2+)-induced swelling was observed, and this inhibition was attenuated by 5-hydroxydecanoate. In isolated ventricular myocytes, pretreatment with Pue prevented ischemia-induced cell death and depolarization of the mitochondrial membrane, and atractyloside and 5-hydroxydecanoate attenuated the effects of Pue. These findings indicate that puerarin protects the myocardium against ischemia and reperfusion injury via inhibiting mitochondrial permeability transition pore opening and activating the mitochondrial ATP-sensitive potassium channel.

Animals↗
PubMed2001

Gas chromatographic-mass spectrometric confirmation of atractyloside in a patient poisoned with Callilepis laureola.

The South African traditional remedy Impila (Callilepis laureola) contains the mitochondrial toxin atractyloside. The plant is sold widely and continues to lead to fatalities in patients. We describe, for the first time, a simple GC-MS procedure for the identification of atractyloside, which we have applied to the gastric washing from a poisoned patient and to extracts of Impila tuber.

Atractyloside↗
PubMed2000

Guanine nucleotide transport by atractyloside-sensitive and -insensitive carriers in isolated heart mitochondria.

In previous work (McKee EE, Bentley AT, Smith RM Jr, and Ciaccio CE, Biochem Biophys Res Commun 257: 466-472, 1999), the transport of guanine nucleotides into the matrix of intact isolated heart mitochondria was demonstrated. In this study, the time course and mechanisms of guanine nucleotide transport are characterized. Two distinct mechanisms of transport were found to be capable of moving guanine nucleotides across the inner membrane. The first carrier was saturable, displayed temperature dependence, preferred GDP to GTP, and did not transport GMP or IMP. When incubated in the absence of exogenous ATP, this carrier had a V(max) of 946 +/- 53 pmol. mg(-1). min(-1) with a K(m) of 2.9 +/- 0.3 mM for GDP. However, transport of GTP and GDP on this carrier was completely inhibited by physiological concentrations of ATP, suggesting that this carrier was not involved with guanine nucleotide transport in vivo. Because transport on this carrier was also inhibited by atractyloside, this carrier was consistent with the well-characterized ATP/ADP translocase. The second mechanism of guanine nucleotide uptake was insensitive to atractyloside, displayed temperature dependence, and was capable of transporting GMP, GDP, and GTP at approximately equal rates but did not transport IMP, guanine, or guanosine. GTP transport via this mechanism was slow, with a V(max) of 48.7 +/- 1.4 pmol. mg(-1). min(-1) and a K(m) = 4.4 +/- 0.4 mM. However, because the requirement for guanine nucleotide transport is low in nondividing tissues such as the heart, this transport process is nevertheless sufficient to account for the matrix uptake of guanine nucleotides and may represent the physiological mechanism of transport.

Adenosine Triphosphate↗
PubMedDate not supplied

Ischemic-like change produced in canine heart by atractyloside: a chemical model.

Experiments were conducted in two canine models. Intracoronary infusion of atractyloside resulted in physiological, biochemical, and ultrastructural changes similar to those seen with ischemia. The fact that atractyloside, a specific inhibitor of adenine nucleotide translocase produces this change in vivo suggests that this inhibition in the key disturbance that initiates the metabolic derangements seen with ischemia. This chemical model seems to provide unique opportunities to study the possible factors that may reverse adenine nucleotide translocase inhibition and thus possibly prevent cell injury.

Animals↗
PubMed1984

Direct photoaffinity labeling of proteins with adenosine 3'-[32P]phosphate 5'-phosphosulfate. Atractyloside inhibits labeling of a Mr = 34,000 protein in an adrenal medullary Golgi fraction.

Direct photoaffinity labeling with radioactively labeled adenosine 3'-phosphate 5'-phosphosulfate (PAPS) followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography was used to identify PAPS binding proteins in a Golgi membrane preparation of bovine adrenal medulla. [3'-32P]PAPS was synthesized from adenosine 5'-phosphosulfate (APS) and [gamma-32P]ATP using APS kinase prepared from yeast and was purified by reverse-phase ion pair high performance liquid chromatography. Upon irradiation with UV light, [3'-32P]PAPS, as well as [35S]PAPS under conditions which minimized sulfotransferase-catalyzed incorporation of 35SO4 from [35S]PAPS into proteins, bound selectively to a 34-kDa protein of the Golgi membrane preparation. PAPS binding to the 34-kDa protein was strongly inhibited by the presence of 50 microM atractyloside. The 34-kDa PAPS binding protein therefore appears to be similar to the mitochondrial ATP/ADP translocator with regard to both molecular weight and inhibition by atractyloside of adenine nucleotide binding. Photoaffinity labeling will be useful in the purification and functional identification of the 34-kDa protein.

Adenine Nucleotides↗
PubMed1984

Effect of atractylosides, palmitoyl coenzyme A, and anion transport inhibitors on translocation of nucleotide sugars and nucleotide sulfate into Golgi vesicles.

The effect of palmitoyl coenzyme A, atractylosides, and anion transport inhibitors on translocation into rat liver Golgi vesicles of adenosine 3'-phosphate 5'-phosphosulfate (PAPS), CMP-N-acetylneuraminic acid, and GDP-fucose was studied. Translocation of the above three nucleotide derivatives was inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS; 50% inhibition required 10-20 microM DIDS). The inhibition of translocation of PAPS by DIDS was used to demonstrate that sulfation of macromolecules within Golgi vesicles is preceded by translocation of PAPS into the vesicles. Palmitoyl coenzyme A, at concentrations below its critical micellar concentration, specifically inhibited translocation into Golgi vesicles of PAPS but not CMP-NeuAc and GDP-fucose. Inhibition of PAPS translocation by 50% required 9 microM palmitoyl coenzyme A. Translocation of PAPS but not of CMP-NeuAc or GDP-fucose was also inhibited by atractyloside or carboxyatractyloside with 50% inhibition requiring 15 microM either glycoside. This pattern of inhibition suggests structural similarities between the putative translocator of PAPS in Golgi membranes and the ATP/ADP translocator of mitochondria.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1996

Fluorometric titration of the mitochondrial ADP/ATP carrier protein in muscle homogenate with atractyloside derivatives.

We describe here the chemical synthesis of the novel methylanthraniloyl (Mant-) derivative of atractyloside (ATR), which is a specific inhibitor of the mitochondrial ADP/ATP carrier. The spectral properties of Mant-ATR and naphthoyl-ATR (N-ATR) are analyzed. Both derivatives bind to the membrane-bound ADP/ATP carrier at the same sites as ATR and carboxyatractyloside (CATR). When Mant-ATR and N-ATR are displaced by CATR, their fluorescence emissions are decreased and increased, respectively. These fluorescence changes allow the titration of the CATR binding sites and therefore the quantitation of the amount of ADP/ATP carrier protein in a biological preparation. The validity of the fluorometric titration was tested with beef heart mitochondria and confirmed by binding assays using radioactive ATR. The fluorometric method was applied to rabbit skeletal muscle homogenate and the results of titration were confirmed by binding assays of radioactive ATR. The reliability of the fluorometric method was assessed by comparing the amounts of CATR binding sites and the content of heme aa3 in muscle homogenates and in isolated mitochondria from the same homogenates. Because of its high sensitivity, the fluorometric titration of the ADP/ATP carrier requires small amounts of tissue. Mant-ATR and N-ATR can therefore be considered as convenient, reliable, and sensitive probes to quantify the amount of ADP/ATP carrier and detect a putative carrier protein deficiency in biopsy samples from human patients suffering from myopathies with no clear identified etiology.

Animals↗
PubMed1999

Inhibition of the ryanodine receptor calcium channel in the sarcoplasmic reticulum of skeletal muscle by an ADP/ATP translocase inhibitor, atractyloside.

The effects of an inhibitor of ADP/ATP translocase (AAT) mainly expressed in the mitochondria inner membrane, atractyloside (ATR), on the gating property of the Ca2+ channels in the sarcoplasmic reticulum (SR) vesicles from the rabbit skeletal muscle were investigated using ion flux measurement and single channel recording. At 10 microM of cytoplasmic Ca2+, ATR decreased the rate constant of choline+ influx through the Ca2+ channels up to about 60% and perfectly inhibited about half the population of single Ca2+ channels incorporated into planar bilayers. Furthermore, the inhibition of the Ca2+ channels by ATR was effective at lower Ca2+. These results support the previous results that AAT exists in the skeletal muscle SR and plays a key role in the Ca2+ mobilization of the skeletal muscle cell [Yamaguchi, N., and Kasai, M. (1998) Biochem. J. 335, 541-547], and the number of Ca2+ channels regulated by AAT is thought to depend on the cytoplasmic Ca2+ concentration.

Animals↗
PubMed1998

Toxicity of atractyloside in precision-cut rat and porcine renal and hepatic tissue slices.

Atractyloside (ATR) causes acute fatal renal and hepatic necrosis in animals and humans. Precision-cut renal cortical and hepatic slices (200 +/- 15 microns) 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-stimulated 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 slices, which was significant at > or = 2 mM, but no changes in liver slices from either species. However, cellular ATP was significantly depleted at > or = 0.2 mM ATR in kidney and in liver slices from both species. ATR also caused a marked leakage of lactate dehydrogenase and alkaline phosphatase from both pig and rat kidney slices at all concentrations, but only lactate dehydrogenase was significantly elevated in liver slices from both species. ATR > or = 0.5 mM caused a significant increase in lipid peroxidation, but only in liver slices of both species, and > or = 0.2 mM ATR caused a marked depletion of reduced glutathione 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 stress may be the cause of toxicity in this organ. Both rat and pig tissue slices from the same organ responded similarly to ATR, although their basal biochemistry was different. ATR toxicity to both kidney and liver showed similar patterns but it appears that the mechanisms of toxicity are different. While cytotoxicity of ATR in kidney is only accompanied with GSH depletion, that of the liver is linked to both lipid peroxidation and GSH depletion. Striated muscle slices from both species were not affected by the highest ATR concentration. This further strengthens the argument that the molecular basis of ATR, target selective toxicity, is not a measure of the interaction between ATR and mitochondria 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 injury for each organ.

Adenosine Triphosphate↗
PubMed1996

Selective cytotoxicity associated with in vitro exposure of fresh rat renal fragments and continuous cell lines to atractyloside.

The consumption of plants containing the diterpenoid atractyloside (ATR) causes selective proximal tubule injury, renal failure and death in humans. We have compared the effects of ATR in freshly isolated renal proximal tubules and glomeruli from rat and also in cell lines: NRK, derived from the proximal tubules, and MDBK and MDCK more closely representing the distal nephron. The effects of ATR (10-500 microM) on proximal tubules and glomeruli were assessed by changes in lipid peroxidation, de novo protein synthesis and the leakage of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), glutamate dehydrogenase (GDH) and N-acetyl-beta-D-glucosaminidase (NAG). The susceptibility of NRK, MDBK and MDCK cell lines to ATR was assessed by the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, measuring mitochondrial reduction. Enzyme leakage was the most sensitive of the markers of cell injury in fresh fragments and ranked LDH > GDH > ALP > NAG in proximal tubules. As little as 20 microM ATR caused significant enzyme leakage from proximal tubules, but there were no increases in enzyme leakage from glomeruli at concentrations < and = 500 microM ATR. De novo protein synthesis was only inhibited 50% at ATR concentration > 5 mM in the proximal tubules, but there were no effects in glomeruli. Malondialdehyde production was significantly elevated at 1 mM ATR for proximal tubules, and 500 microM for glomeruli. NRK cells were sensitive to ATR (IC50, 120 microM), but MDBK or MDCK cells were unaffected by < and = 1 mM of this diterpenoid. Both freshly isolated fragments and continuous cell lines representing the proximal tubules are more sensitive to ATR than either glomeruli or cells representing the distal nephron. These data also show that protein synthesis is a less specific and sensitive measure of ATR cytotoxicity than enzyme leakage in fragments. MTT reduction to formazan was the most sensitive in the NRK cell line. The low levels of lipid peroxidation products in proximal tubular fragments or sensitive renal cell lines at toxic levels of ATR suggest that oxidative injury is not a key mechanism.

Animals↗
PubMed1983

Synthesis and properties of fluorescent derivatives of atractyloside as potential probes of the mitochondrial ADP/ATP carrier protein.

The chemical synthesis of fluorescent derivatives of atractyloside (ATR), an inhibitor of the mitochondrial ADP/ATP carrier protein, is described. These derivatives are the following: 6'-O-dansyl ATR, 6'-O-dansyl-aminobutyryl ATR, and 6'-O-naphthoyl ATR. The spectral properties of these analogs were analyzed, and their biological features were compared to those of ATR. The fluorescence emission of the dansyl ATR derivatives was increased in organic solvents and that of naphthoyl ATR was decreased; for both analogs, solubilization in organic solvents resulted in a blue shift of the emission peak. The fluorescent dansyl and naphthoyl ATR derivatives were specifically recognized by the mitochondrial ADP/ATP carrier protein. Because of their spectral properties and their biochemical reactivities, the fluorescent analogs of ATR can be considered as potential probes to investigate the topography of the ADP/ATP carrier in the mitochondrial membrane and to monitor conformational changes of the ADP/ATP carrier protein associated with transport.

Adenosine Diphosphate↗
PubMed1986

Adenine nucleotide compartmentation in foetal rat hepatocytes. Effects of atractyloside, oligomycin, calcium ionophore and adrenergic agonists.

In the presence of lactate plus pyruvate, or glucose or alanine as substrates, ATP/ADP ratios in the cytosol were higher than in mitochondria in isolated rat foetal hepatocytes. The cytosolic ATP/ADP ratios were dependent on substrate (lactate + pyruvate greater than glucose greater than alanine). Oleate increased the cytosolic ATP/ADP ratios in the presence of the other substrates studied. Atractyloside decreased the cytosolic ATP/ADP ratios, oligomycin decreasing these values in both compartments. Isoproterenol, phenylephrine and Ca2+ ionophore decreased the cytosolic ATP/ADP ratio, without altering this value in mitochondria.

Adenine Nucleotides↗
PubMed1993

Extrarenal and direct renal actions of atractyloside contribute to its acute nephrotoxicity in pentobarbital-anesthetized dogs.

Acute extrarenal and renal changes were noted following the intravenous administration of atractyloside (ATR) (12.97 and 32.40 mumol/kg) to spontaneously-respiring, pentobarbital-anesthetized dogs. Severe hypoglycemia, respiratory depression and hypoxemia developed within 2 h. These extrarenal changes were accompanied by adverse changes in renal function, ultrastructural damage to S1, S2 and S3 cells of the proximal tubule and to thick ascending limb cells and an impaired ability of the kidneys to respond to a known diuretic--ethacrynic acid (EA). Mechanical ventilation of ATR-treated pentobarbital-anesthetized dogs circumvented the development of hypoxemia and all but eliminated the toxicity to S3 and thick ascending limb cells, thereby establishing that ATR's extrarenal actions contributed to its nephrotoxicity. On the other hand, direct renal actions of ATR were evident following its administration into the renal artery; certain important extrarenal effects were minimized, while adverse changes in renal function and ultrastructure of S1 and S2 cells were noted primarily in the ipsilateral kidney. The high degree of variability associated with ATR's systemic toxicity was confirmed and a similar degree of variability in its renal toxicity was established. Our results emphasize the importance of evaluating the extrarenal effects produced by any toxicant when determining its nephrotoxic potential.

Anesthesia↗
PubMed2006

Bongkrekic acid and atractyloside inhibits chloride channels from mitochondrial membranes of rat heart.

The aim of this work was to characterize the effect of bongkrekic acid (BKA), atractyloside (ATR) and carboxyatractyloside (CAT) on single channel properties of chloride channels from mitochondria. Mitochondrial membranes isolated from a rat heart muscle were incorporated into a bilayer lipid membrane (BLM) and single chloride channel currents were measured in 250/50 mM KCl cis/trans solutions. BKA (1-100 microM), ATR and CAT (5-100 microM) inhibited the chloride channels in dose-dependent manner. The inhibitory effect of the BKA, ATR and CAT was pronounced from the trans side of a BLM and it increased with time and at negative voltages (trans-cis). These compounds did not influence the single channel amplitude, but decreased open dwell time of channels. The inhibitory effect of BKA, ATR and CAT on the mitochondrial chloride channel may help to explain some of their cellular and/or subcellular effects.

Animals↗