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Jeanmichel Richard - One of the best experts on this subject based on the ideXlab platform.
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dna strand scission by the nephrotoxin 2 2 bipyridine 3 3 4 4 tetrol 1 1 dioxide and related compounds in the presence of iron
Free Radical Research, 2000Co-Authors: Danielle Cantinesnault, Hammou Oubrahim, Jeanmichel RichardAbstract:The capacity of non-illuminated nephrotoxin Orellanine ([2,2′-bipyridine]-3,3′,4,4′-tetrol-1,1′-dioxide) to induce DNA damage in the presence of ferrous iron and dioxygen has been evaluated. Maximal single-strand breaks in plasmid DNA were obtained with a metal to ligand ratio 1:3. Instantaneous oxidation of Fe2+ in presence of Orellanine under air was responsible for oxy-radical production concomitant to a stable ferric complex Fe(III)Or3 formation, leading to oxidative DNA breakage at physiological pH. DNA damage was lowered in the presence of SOD and catalase or DMSO, indicating a set of reactions that leads to oxyradical generation. Iron chelators such as DTPA and EDTA had no protecting effect, Desferal slightly protected. GSH acted as an oxy-radical scavenger, whereas cysteine induced stronger damage.Closely related bipyridine compounds were also studied in presence of Fe2+ and O2 using a combination of spin-trapping and DNA-nicking experiments, none of which were able to chelate iron and induce dama...
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generation of oxygen radicals from iron complex of Orellanine a mushroom nephrotoxin preliminary esr and spin trapping stukes
Free Radical Research, 1998Co-Authors: Danelle Cantinesnault, Jeanmichel Richard, Andre JeunetAbstract:Orellanine, [2,2′-bipyridine]-3,3′,4,4′-tetrol-l,I'-dioxide, is the toxin responsible for the lethal nephrotoxicity of some Cortinarius mushrooms. Our present ESR and spin-trapping studies of the redox properties of the system of non-illuminated Orellanine, ferrous iron and dioxygen contribute to understanding the molecular mechanism of its toxicity. UV-visible spectrophoto-metry, cyclic voltammetry and ESR in frozen medium showed the formation of a wine-red tris complex, Fe(III)Or3. This ferric complex is easily reducible (EP =-565 mV vs Ag/AgCl/3M KCl at pH7), involving a one-electron reversible process. Spin-trapping using DMPO is employed to detect the generation of super-oxide anion and hydroxyl radicals. The instantaneous one-electron oxidation of ferrous ions in the presence of the toxin under air is concomitant with dioxygen consumption as supported by dioxygen consumption. GSH involves the toxin and ferrous ions under air in a redox cycling process resulting in the production of glutathionyl and ...
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peroxidase mediated oxidation a possible pathway for activation of the fungal nephrotoxin Orellanine and related compounds esr and spin trapping studies
Free Radical Research, 1998Co-Authors: Hammou Oubrahim, Jeanmichel Richard, Danielle CantinesnaultAbstract:Orellanine is the tetrahydroxylated and di-N-oxidized bipyridine toxin extracted from several Cortinarius mushrooms among them C. orellanus. The pathogenic mechanism involved in the C. orellanus-poisoning by Orellanine leading to kidney impairment is not yet fully understood until now. Electron spin resonance (ESR) spectroscopy has been used to study the activation of Orellanine by horseradish peroxidase/H2O2 system at physiological pH. Evidence for a one-electron oxidation of the toxin by this enzymatic system to an ortho-semiquinone radical intermediate is presented.The Orellanine ortho-semiquinone generated by the peroxidase/H2O2 system abstracts hydrogen from glutathione, generating the glutathionyl radical which is spin-trapped by 5,5′-dimethyl-1-pyrroline N-oxide (DMPO) and subsequently detected by ESR spectroscopy. Similarly, the ortho-semiquinone abstracts hydrogen from ascorbic acid to generate the ascorbyl radical which is detected by direct ESR. The peroxidatic oxidation of Orellanine to semiqu...
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first electron spin resonance evidence for the production of semiquinone and oxygen free radicals from Orellanine a mushroom nephrotoxin
Free Radical Biology and Medicine, 1995Co-Authors: Jeanmichel Richard, Danielle Cantinesnault, Andre JeunetAbstract:Orellanine is the tetrahydroxylated and di-N-oxidized bipyridine toxin from several Cortinarius mushrooms. The mechanism responsible for its lethal nephrotoxicity was unknown until now. Our present ESR spectroscopic study of the redox properties of the toxin is an original contribution to the knowledge of its toxicity. It was achieved in particular by comparison of the properties of Orellanine to that of other bipyridine compounds. After a one-electron oxidation (e.g., photochemical oxidation upon visible light), a radical form of Orellanine is observed at physiological pH under aerobic or anaerobic conditions. This radical, identified as ortho-semiquinone anion radical, can also be generated by oxidation with biological oxidizing agents or enzymatic systems. Production of superoxide and hydroxyl radicals is shown by the spin-trapping method using DMPO as a spin trap. Bioreducing agents like GSH and cysteine involve in vitro the semiquinone radical and Orellanine in a redox cycling process resulting in the production of glutathionyl and oxygen free radicals. This process leads in vitro to a large oxygen consumption and to a dramatic depletion of glutathione level. The formation of an apparently stable ortho-semiquinone anion radical and of reactive oxygen radical species is observed for the first time with a mushroom toxin. It is due to the catechol-like functions borne by the di-N-oxidized bipyridine structure of the toxin and may at least partly explain the toxicity of Orellanine.
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Orellanine inhibits protein synthesis in madin darby canine kidney cells in rat liver mitochondria and in vitro indication for its activation prior to in vitro inhibition
Toxicology, 1991Co-Authors: Jeanmichel Richard, E E Creppy, Jeanlouis Benoitguyod, Guy DirheimerAbstract:Abstract Pure Orellanine, a nephrotoxic compound extracted from the mushroom Cortinarius orellanus , which is known to induce severe kidney damage several days or weeks after ingestion, is found to inhibit strongly the synthesis of macromolecules (Proteins, RNA and DNA) in Madin-Darby canine kidney (MDCK) cells and in rat liver mitochondria, although the uptake of labelled precursors of the above macromolecules is not significantly altered. Direct addition of Orellanine to a cell-free system of rabbit reticulocyte lysate does not produce any inhibition of protein synthesis. However, when Orellanine is pre-incubated with activating rat liver microsomal systems, this inhibition occurs. Thus, the in vivo inhibition of protein synthesis is most likely due to a metabolite of Orellanine.
Wilson K Rumbeiha - One of the best experts on this subject based on the ideXlab platform.
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improved tissue based analytical test methods for Orellanine a biomarker of cortinarius mushroom intoxication
Toxins, 2016Co-Authors: Poojya Anantharam, Dahai Shao, Shusheng Tang, Paula M Imerman, Dwayne E Schrunk, Eric R Burrough, Tsevelmaa Sedkhuu, Wilson K RumbeihaAbstract:Orellanine (OR) toxin is produced by mushrooms of the genus Cortinarius which grow in North America and in Europe. OR poisoning is characterized by severe oliguric acute renal failure, with a mortality rate of 10%-30%. Diagnosis of OR poisoning currently hinges on a history of ingestion of Cortinarius mushrooms and histopathology of renal biopsies. A key step in the diagnostic approach is analysis of tissues for OR. Currently, tissue-based analytical methods for OR are nonspecific and lack sensitivity. The objectives of this study were: (1) to develop definitive HPLC and LC-MS/MS tissue-based analytical methods for OR; and (2) to investigate toxicological effects of OR in mice. The HPLC limit of quantitation was 10 µg/g. For fortification levels of 15 µg/g to 50 µg/g OR in kidney, the relative standard deviation was between 1.3% and 9.8%, and accuracy was within 1.5% to 7.1%. A matrix-matched calibration curve was reproduced in this range with a correlation coefficient (r) of 0.97-0.99. The limit of detection was 20 ng/g for LC-MS/MS. In OR-injected mice, kidney OR concentrations were 97 ± 51 µg/g on Day 0 and 17 ± 1 µg/g on termination Day 3. Splenic and liver injuries were novel findings in this mouse model. The new tissue-based analytical tests will improve diagnosis of OR poisoning, while the mouse model has yielded new data advancing knowledge on OR-induced pathology. The new tissue-based analytical tests will improve diagnosis of OR poisoning, while the mouse model has yielded new data advancing knowledge on OR-induced pathology.
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a novel Orellanine containing mushroom cortinarius armillatus
Toxicon, 2016Co-Authors: Dahai Shao, Shusheng Tang, Rosanne A Healy, Paula M Imerman, Dwayne E Schrunk, Wilson K RumbeihaAbstract:Orellanine (3,3',4,4'-tetrahydroxy-2,2'-bipyridine-1,1'-dioxide) is a tetrahydroxylated di-N-oxidized bipyridine compound. The toxin, present in certain species of Cortinarius mushrooms, is structurally similar to herbicides Paraquat and Diquat. Cortinarius orellanus and Cortinarius rubellus are the major Orellanine-containing mushrooms. Cortinarius mushrooms are widely reported in Europe where they have caused human poisoning and deaths through accidental ingestion of the poisonous species mistaken for the edible ones. In North America, Cortinarius orellanosus mushroom poisoning was recently reported to cause renal failure in a Michigan patient. Cortinarius mushroom poisoning is characterized by delayed acute renal failure, with some cases progressing to end-stage kidney disease. There is debate whether other Cortinarius mushroom contain Orellanine or not, especially in North America. Currently, there are no veterinary diagnostic laboratories in North America with established test methods for detection and quantitation of Orellanine. We have developed two diagnostic test methods based on HPLC and LC-MSMS for identification and quantitation of Orellanine in mushrooms. Using these methods, we have identified Cortinarius armillatus as a novel Orellanine-containing mushroom in North America. The mean toxin concentration of 145 ug/g was <1% of that of the more toxic C. rubellus. The HPLC method can detect Orellanine at 17 μg g(-1) while the LC-MSMS method is almost 2000 times more sensitive and can detect Orellanine at 30 ng g(-1). Both tests are quantitative, selective and are now available for veterinary diagnostic applications.
Danielle Cantinesnault - One of the best experts on this subject based on the ideXlab platform.
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dna strand scission by the nephrotoxin 2 2 bipyridine 3 3 4 4 tetrol 1 1 dioxide and related compounds in the presence of iron
Free Radical Research, 2000Co-Authors: Danielle Cantinesnault, Hammou Oubrahim, Jeanmichel RichardAbstract:The capacity of non-illuminated nephrotoxin Orellanine ([2,2′-bipyridine]-3,3′,4,4′-tetrol-1,1′-dioxide) to induce DNA damage in the presence of ferrous iron and dioxygen has been evaluated. Maximal single-strand breaks in plasmid DNA were obtained with a metal to ligand ratio 1:3. Instantaneous oxidation of Fe2+ in presence of Orellanine under air was responsible for oxy-radical production concomitant to a stable ferric complex Fe(III)Or3 formation, leading to oxidative DNA breakage at physiological pH. DNA damage was lowered in the presence of SOD and catalase or DMSO, indicating a set of reactions that leads to oxyradical generation. Iron chelators such as DTPA and EDTA had no protecting effect, Desferal slightly protected. GSH acted as an oxy-radical scavenger, whereas cysteine induced stronger damage.Closely related bipyridine compounds were also studied in presence of Fe2+ and O2 using a combination of spin-trapping and DNA-nicking experiments, none of which were able to chelate iron and induce dama...
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peroxidase mediated oxidation a possible pathway for activation of the fungal nephrotoxin Orellanine and related compounds esr and spin trapping studies
Free Radical Research, 1998Co-Authors: Hammou Oubrahim, Jeanmichel Richard, Danielle CantinesnaultAbstract:Orellanine is the tetrahydroxylated and di-N-oxidized bipyridine toxin extracted from several Cortinarius mushrooms among them C. orellanus. The pathogenic mechanism involved in the C. orellanus-poisoning by Orellanine leading to kidney impairment is not yet fully understood until now. Electron spin resonance (ESR) spectroscopy has been used to study the activation of Orellanine by horseradish peroxidase/H2O2 system at physiological pH. Evidence for a one-electron oxidation of the toxin by this enzymatic system to an ortho-semiquinone radical intermediate is presented.The Orellanine ortho-semiquinone generated by the peroxidase/H2O2 system abstracts hydrogen from glutathione, generating the glutathionyl radical which is spin-trapped by 5,5′-dimethyl-1-pyrroline N-oxide (DMPO) and subsequently detected by ESR spectroscopy. Similarly, the ortho-semiquinone abstracts hydrogen from ascorbic acid to generate the ascorbyl radical which is detected by direct ESR. The peroxidatic oxidation of Orellanine to semiqu...
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first electron spin resonance evidence for the production of semiquinone and oxygen free radicals from Orellanine a mushroom nephrotoxin
Free Radical Biology and Medicine, 1995Co-Authors: Jeanmichel Richard, Danielle Cantinesnault, Andre JeunetAbstract:Orellanine is the tetrahydroxylated and di-N-oxidized bipyridine toxin from several Cortinarius mushrooms. The mechanism responsible for its lethal nephrotoxicity was unknown until now. Our present ESR spectroscopic study of the redox properties of the toxin is an original contribution to the knowledge of its toxicity. It was achieved in particular by comparison of the properties of Orellanine to that of other bipyridine compounds. After a one-electron oxidation (e.g., photochemical oxidation upon visible light), a radical form of Orellanine is observed at physiological pH under aerobic or anaerobic conditions. This radical, identified as ortho-semiquinone anion radical, can also be generated by oxidation with biological oxidizing agents or enzymatic systems. Production of superoxide and hydroxyl radicals is shown by the spin-trapping method using DMPO as a spin trap. Bioreducing agents like GSH and cysteine involve in vitro the semiquinone radical and Orellanine in a redox cycling process resulting in the production of glutathionyl and oxygen free radicals. This process leads in vitro to a large oxygen consumption and to a dramatic depletion of glutathione level. The formation of an apparently stable ortho-semiquinone anion radical and of reactive oxygen radical species is observed for the first time with a mushroom toxin. It is due to the catechol-like functions borne by the di-N-oxidized bipyridine structure of the toxin and may at least partly explain the toxicity of Orellanine.
Andre Jeunet - One of the best experts on this subject based on the ideXlab platform.
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generation of oxygen radicals from iron complex of Orellanine a mushroom nephrotoxin preliminary esr and spin trapping stukes
Free Radical Research, 1998Co-Authors: Danelle Cantinesnault, Jeanmichel Richard, Andre JeunetAbstract:Orellanine, [2,2′-bipyridine]-3,3′,4,4′-tetrol-l,I'-dioxide, is the toxin responsible for the lethal nephrotoxicity of some Cortinarius mushrooms. Our present ESR and spin-trapping studies of the redox properties of the system of non-illuminated Orellanine, ferrous iron and dioxygen contribute to understanding the molecular mechanism of its toxicity. UV-visible spectrophoto-metry, cyclic voltammetry and ESR in frozen medium showed the formation of a wine-red tris complex, Fe(III)Or3. This ferric complex is easily reducible (EP =-565 mV vs Ag/AgCl/3M KCl at pH7), involving a one-electron reversible process. Spin-trapping using DMPO is employed to detect the generation of super-oxide anion and hydroxyl radicals. The instantaneous one-electron oxidation of ferrous ions in the presence of the toxin under air is concomitant with dioxygen consumption as supported by dioxygen consumption. GSH involves the toxin and ferrous ions under air in a redox cycling process resulting in the production of glutathionyl and ...
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first electron spin resonance evidence for the production of semiquinone and oxygen free radicals from Orellanine a mushroom nephrotoxin
Free Radical Biology and Medicine, 1995Co-Authors: Jeanmichel Richard, Danielle Cantinesnault, Andre JeunetAbstract:Orellanine is the tetrahydroxylated and di-N-oxidized bipyridine toxin from several Cortinarius mushrooms. The mechanism responsible for its lethal nephrotoxicity was unknown until now. Our present ESR spectroscopic study of the redox properties of the toxin is an original contribution to the knowledge of its toxicity. It was achieved in particular by comparison of the properties of Orellanine to that of other bipyridine compounds. After a one-electron oxidation (e.g., photochemical oxidation upon visible light), a radical form of Orellanine is observed at physiological pH under aerobic or anaerobic conditions. This radical, identified as ortho-semiquinone anion radical, can also be generated by oxidation with biological oxidizing agents or enzymatic systems. Production of superoxide and hydroxyl radicals is shown by the spin-trapping method using DMPO as a spin trap. Bioreducing agents like GSH and cysteine involve in vitro the semiquinone radical and Orellanine in a redox cycling process resulting in the production of glutathionyl and oxygen free radicals. This process leads in vitro to a large oxygen consumption and to a dramatic depletion of glutathione level. The formation of an apparently stable ortho-semiquinone anion radical and of reactive oxygen radical species is observed for the first time with a mushroom toxin. It is due to the catechol-like functions borne by the di-N-oxidized bipyridine structure of the toxin and may at least partly explain the toxicity of Orellanine.
Börje Haraldsson - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic Properties of the Nephrotoxin Orellanine in Rats.
Toxins, 2018Co-Authors: Deman Najar, Börje Haraldsson, Jenny Nyström, Annika Thorsell, Carina Sihlbom, Kerstin EbeforsAbstract:Orellanine is a nephrotoxin found in mushrooms of the Cortinarius family. Accidental intake of this substance may cause renal failure. Orellanine is specific for proximal tubular cells and could, therefore, potentially be used as treatment for metastatic renal cancer, which originates from these cells. However, more information is needed about the distribution and elimination of Orellanine from the body to understand its potential use for therapy. In this study, 5 mg/kg Orellanine (unlabeled and ³H-labeled) was injected intravenously in rats (Wistar and Sprague Dawley). Distribution was measured (Wistar rats, n = 10, n = 12) using radioluminography and the highest amount of Orellanine was found in the kidney cortex and bladder at all time-points investigated. The pharmacokinetic properties of Orellanine was investigated using LC-MS/MS and β-scintillation to measure the amount of Orellanine in plasma. Three groups of rats were investigated: control rats with intact kidneys (n = 10) and two groups with bilateral renal artery ligation (n = 7) where animals in one of these groups were treated with peritoneal dialysis (n = 8). Using LC-MS/MS, the half-life of Orellanine was found to be 109 ± 6 min in the controls. In the groups with ligated renal arteries, Orellanine had a half-life of 756 ± 98 min without and 238 ± 28 min with dialysis. Thus, Orellanine was almost exclusively eliminated by glomerular filtration as well as by peritoneal dialysis.
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Pharmacokinetic Properties of the Nephrotoxin Orellanine in Rats
MDPI AG, 2018Co-Authors: Deman Najar, Börje Haraldsson, Jenny Nyström, Annika Thorsell, Carina Sihlbom, Kerstin EbeforsAbstract:Orellanine is a nephrotoxin found in mushrooms of the Cortinarius family. Accidental intake of this substance may cause renal failure. Orellanine is specific for proximal tubular cells and could, therefore, potentially be used as treatment for metastatic renal cancer, which originates from these cells. However, more information is needed about the distribution and elimination of Orellanine from the body to understand its potential use for therapy. In this study, 5 mg/kg Orellanine (unlabeled and 3H-labeled) was injected intravenously in rats (Wistar and Sprague Dawley). Distribution was measured (Wistar rats, n = 10, n = 12) using radioluminography and the highest amount of Orellanine was found in the kidney cortex and bladder at all time-points investigated. The pharmacokinetic properties of Orellanine was investigated using LC-MS/MS and β-scintillation to measure the amount of Orellanine in plasma. Three groups of rats were investigated: control rats with intact kidneys (n = 10) and two groups with bilateral renal artery ligation (n = 7) where animals in one of these groups were treated with peritoneal dialysis (n = 8). Using LC-MS/MS, the half-life of Orellanine was found to be 109 ± 6 min in the controls. In the groups with ligated renal arteries, Orellanine had a half-life of 756 ± 98 min without and 238 ± 28 min with dialysis. Thus, Orellanine was almost exclusively eliminated by glomerular filtration as well as by peritoneal dialysis
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Long-term clinical outcome for patients poisoned by the fungal nephrotoxin Orellanine.
BMC nephrology, 2017Co-Authors: Heidi Hedman, Johan Holmdahl, Johan Mölne, Kerstin Ebefors, Börje Haraldsson, Jenny NyströmAbstract:Accidental intake of mushrooms of the Cortinarius species (deadly webcap) may cause irreversible renal damage and the need for dialysis or transplantation. The species is found in forests of Northern Europe, Scandinavia and North America and may be mistaken for other edible mushrooms. The highly selective nephrotoxic compound of the mushroom is called Orellanine. Very little is known about the long-term effects of the nephrotoxin. We identified patients who ingested deadly webcap in the period of 1979 to 2012. Informed consent and medical records were obtained for 28 of the 39 cases that occurred during the 34-year period. A case control group was also studied based on sex, age and initiation of dialysis or transplantation. The average age at time of the accidental intake was 40 ± 3 (n = 28) years. 64% of patients were male, and 22 of 28 patients developed acute kidney injury requiring dialysis. Serum creatinine peaked at 1 329 ± 133 μmol/l, and serum urea was 31 ± 3.5 mmol/l. No signs of acute damage were present in any other organ. The average time of follow-up was 16.9 ± 2.1 years (1.24–34.3 years, n = 28). 15 patients were transplanted and 3 also had a second graft. At follow-up, 23 patients were alive, and five had died at ages of 67 ± 5 (range 54–84). The outcome was similar in the case control group with 6 deaths in 20 patients. We conclude that the long-term prognosis for patients poisoned by deadly webcap who lost their renal function is not different compared to other patients in active uremic care.
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Long-term clinical outcome for patients poisoned by the fungal nephrotoxin Orellanine
BMC, 2017Co-Authors: Heidi Hedman, Johan Holmdahl, Johan Mölne, Kerstin Ebefors, Börje Haraldsson, Jenny NyströmAbstract:Abstract Background Accidental intake of mushrooms of the Cortinarius species (deadly webcap) may cause irreversible renal damage and the need for dialysis or transplantation. The species is found in forests of Northern Europe, Scandinavia and North America and may be mistaken for other edible mushrooms. The highly selective nephrotoxic compound of the mushroom is called Orellanine. Very little is known about the long-term effects of the nephrotoxin. Methods We identified patients who ingested deadly webcap in the period of 1979 to 2012. Informed consent and medical records were obtained for 28 of the 39 cases that occurred during the 34-year period. A case control group was also studied based on sex, age and initiation of dialysis or transplantation. Results The average age at time of the accidental intake was 40 ± 3 (n = 28) years. 64% of patients were male, and 22 of 28 patients developed acute kidney injury requiring dialysis. Serum creatinine peaked at 1 329 ± 133 μmol/l, and serum urea was 31 ± 3.5 mmol/l. No signs of acute damage were present in any other organ. The average time of follow-up was 16.9 ± 2.1 years (1.24–34.3 years, n = 28). 15 patients were transplanted and 3 also had a second graft. At follow-up, 23 patients were alive, and five had died at ages of 67 ± 5 (range 54–84). The outcome was similar in the case control group with 6 deaths in 20 patients. Conclusion We conclude that the long-term prognosis for patients poisoned by deadly webcap who lost their renal function is not different compared to other patients in active uremic care
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Analysis of the mushroom nephrotoxin Orellanine and its glucosides.
Journal of natural products, 2012Co-Authors: Anders Herrmann, Heidi Hedman, Börje Haraldsson, Johan Rosén, Daniel Jansson, Karl-erik HellenäsAbstract:Orellanine is a nephrotoxin found in various Cortinaceae mushroom species. Unintentional consumption after these species were confused with edible mushrooms such as Cantharellus tubaeformis has caused several casualties. In this work, a quantitative HPLC-ESI-MS/MS method for total Orellanine in Cortinarius rubellus, spiked blood plasma, and a mushroom stew prepared from C. tubaeformis with the addition of a single specimen of C. rubellus is presented. The existence of mono- and diglucosylated Orellanine in C. rubellus was also proven, although quantitative analysis could not be obtained for the glucosides due to rapid hydrolyzation to Orellanine in the extract. Extraction with 3 M HCl or water mainly yielded Orellanine, while MeOH or acidified MeOH mainly extracted mono- and diglucosylated Orellanine. The highest recovery of total Orellanine was obtained with 3 M HCl, which was subsequently used for quantitative analysis. A C18 HPLC column and low pH in the eluents retained all these toxins. Orellanine co...