Free radical reactions might contribute to severe alpha amanitin hepatotoxicity – A hypothesis

Zheleva, A.; Toleкova, A.; Zhelev, Momchil; Uzunova, Veselina; Platikanova, Magdalena; Gadzheva, Vesselina

doi:10.1016/j.mehy.2006.10.066

Cited by 53 publications

(52 citation statements)

References 26 publications

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“…α-Amanitin causes its hepatotoxicity primarily by RNA polymerase II inhibition (24,25). In a study conducted by Zheleva et al in 2007, it was suggested that increased ROS load and oxidative stress might be involved in α-amanitin-induced hepatotoxicity, in addition to the previously identified pathophysiological mechanism (15). A small number of other studies have supported the relationship between increased oxidative stress and α-amanitin-induced hepatotoxicity (6,7,(16)(17)(18).…”

Section: Histopathological Assessmentmentioning

confidence: 93%

“…In a mouse α-amanitin poisoning study, Zheleva et al reported the same levels of SOD activity in the 0.5 mg/kg α-amanitin and control groups and a higher level in the 1.0 mg/ kg α-amanitin group than the controls at 20 h after exposure (15). The SOD activity of human hepatocytes treated with α-amanitin was reportedly significantly higher than controls at 48 h (7).…”

Section: Histopathological Assessmentmentioning

confidence: 99%

“…We found GPx activity in low-and moderate-dose α-amanitin poisoning to be slightly higher than in the controls, but its activity was the same in moderate-and high-dose poisoning groups. In the current literature, investigators have tended not to evaluate hepatocyte GPx activity in α-amanitin poisoning, because they indicated that GPx was responsible for decomposition of H 2 O 2 at low levels of H 2 O 2 and that CAT was responsible at high levels of H 2 O 2 (15,16,29). Conversely, it has been reported that increased ROS load and decreased glutathione levels might play an important role in hepatocyte necrosis induced by toxins, including paracetamol and α-amanitin (26,30 production due to increased SOD activity, and GPx was also involved in the antioxidant mechanisms fighting against an increased ROS load.…”

Section: Histopathological Assessmentmentioning

confidence: 99%

“…The role of increased oxidative stress has been demonstrated in experimental organophosphate, paracetamol, and methotrexate models (12)(13)(14). Recent in vitro and in vivo studies have suggested that oxidative stress is probably responsible for α-amanitininduced hepatotoxicity in studies (7,(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

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The role of oxidative stress in α-amanitin-induced hepatotoxicityin an experimental mouse model

et al. 2017

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Background/aim: This study aimed to evaluate oxidative stress markers of liver tissue in a mouse α-amanitin poisoning model with three different toxin levels. Materials and methods:The mice were randomly divided into Group 1 (control), Group 2 (0.2 mg/kg), Group 3 (0.6 mg/kg), and Group 4 (1.0 mg/kg). The toxin was injected intraperitoneally and 48 h of follow-up was performed before sacrifice.Results: Median superoxide dismutase activities of liver tissue in Groups 3 and 4 were significantly higher than in Group 1 (for both, P = 0.001). The catalase activity in Group 2 was significantly higher, but in Groups 3 and 4 it was significantly lower than in Group 1

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Section: Histopathological Assessmentmentioning

confidence: 93%

Section: Histopathological Assessmentmentioning

confidence: 99%

Section: Histopathological Assessmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The role of oxidative stress in α-amanitin-induced hepatotoxicityin an experimental mouse model

et al. 2017

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“…Kawaji et al (1990) investigating amatoxins-producing mushroom toxicity in isolated rat hepatocytes showed that extract of Amanita virosa markedly decreased intracellular glutathione content. Moreover, according to some reports free radical formation might contribute to the severe amatoxin hepatotoxicity (Magdalan et al, 2008;Zheleva et al, 2007). Since there are no reports on standard dosage regimen in mushroom poisoning, we tested ACC in concentrations corresponding to its plasma levels after the recommended dosage during the treatment in acetaminophen toxicity.…”

Section: Discussionmentioning

confidence: 99%

Benzylpenicillin, acetylcysteine and silibinin as antidotes in human hepatocytes intoxicated with α-amanitin

Magdalan

Ostrowska

Piotrowska

et al. 2010

Experimental and Toxicologic Pathology

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International audienceFatalities due to mushroom poisonings are increasing worldwide, with high mortality rate resulting from ingestion of amanitin-producing species. Intoxications caused by amanitin-containing mushrooms represent an unresolved problem in clinical toxicology since no specific and fully efficient antidote is available. The objective of this study was a comparative evaluation of benzylpenicillin (BPCN), acetylcysteine (ACC) and silibinin (SIL) as an antidotes in human hepatocytes intoxicated with α-amanitin (α-AMA)

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A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B

et al. 2015

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Amanita phalloides is responsible for more than 90 % of mushroom-related fatalities, and no effective antidote is available. α-Amanitin, the main toxin of A. phalloides, inhibits RNA polymerase II (RNAP II), causing hepatic and kidney failure. In silico studies included docking and molecular dynamics simulation coupled to molecular mechanics with generalized Born and surface area method energy decomposition on RNAP II. They were performed with a clinical drug that shares chemical similarities to α-amanitin, polymyxin B. The results show that polymyxin B potentially binds to RNAP II in the same interface of α-amanitin, preventing the toxin from binding to RNAP II. In vivo, the inhibition of the mRNA transcripts elicited by α-amanitin was efficiently reverted by polymyxin B in the kidneys. Moreover, polymyxin B significantly decreased the hepatic and renal α-amanitin-induced injury as seen by the histology and hepatic aminotransferases plasma data. In the survival assay, all animals exposed to α-amanitin died within 5 days, whereas 50 % survived up to 30 days when polymyxin B was administered 4, 8, and 12 h post-α-amanitin. Moreover, a single dose of polymyxin B administered concomitantly with α-amanitin was able to guarantee 100 % survival. Polymyxin B protects RNAP II from inactivation leading to an effective prevention of organ damage and increasing survival in α-amanitin-treated animals. The present use of clinically relevant concentrations of an already human-use-approved drug prompts the use of polymyxin B as an antidote for A. phalloides poisoning in humans.

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Free radical reactions might contribute to severe alpha amanitin hepatotoxicity – A hypothesis

Cited by 53 publications

References 26 publications

The role of oxidative stress in α-amanitin-induced hepatotoxicityin an experimental mouse model

The role of oxidative stress in α-amanitin-induced hepatotoxicityin an experimental mouse model

Benzylpenicillin, acetylcysteine and silibinin as antidotes in human hepatocytes intoxicated with α-amanitin

A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B

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