Glutathione Depletion by Phorone Organ Specificity and Effect on Hepatic Microsomal Mixed-Function Oxidase System

Younes, Maged; Sharma, Satish C.; Siegers, C.‐P.

doi:10.3109/01480548609042831

Cited by 22 publications

(5 citation statements)

References 16 publications

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“…In a recent study we showed that potassium bromate activated the Nrf2 and p53 response without activation of the ATF4 response (Limonciel et al, 2018 ). Phorone can similarly activate Nrf2 due to glutathione depletion (Younes et al, 1986 ; Iannone et al, 1990 ; Oguro et al, 1996 ). Tunicamycin is a prototypical activator of the unfolded protein response (including the ATF4 branch) by causing an accumulation of misfolded glycoproteins in the ER (Oslowski and Urano, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases

et al. 2018

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Toxicological responses to chemical insult are largely regulated by transcriptionally activated pathways that may be independent, correlated and partially or fully overlapping. Investigating the dynamics of the interactions between stress responsive transcription factors from toxicogenomic data and defining the signature of each of them is an additional step toward a system level understanding of perturbation driven mechanisms. To this end, we investigated the segregation of the genes belonging to the three following transcriptionally regulated pathways: the AhR pathway, the Nrf2 pathway and the ATF4 pathway. Toxicogenomic datasets from three projects (carcinoGENOMICS, Predict-IV and TG-GATEs) obtained in various experimental conditions (in human and rat in vitro liver and kidney models and rat in vivo, with bolus administration and with repeated doses) were combined and consolidated where overlaps between datasets existed. A bioinformatic analysis was performed to refine pathways' signatures and to create chemical activation capacity scores to classify chemicals by their potency and selectivity of activation of each pathway. With some refinement such an approach may improve chemical safety classification and allow biological read across on a pathway level.

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Section: Introductionmentioning

confidence: 99%

Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases

et al. 2018

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“…Cytochrome P-450 content, NADPH-cytochrome c reductase activity, aminopyrine demethylation capacity, as well as the production of . O 2 -and H 2 O 2 were unaffected by phorone treatment (Younes et al, 1986). Phorone treatment also had no effect on lipid peroxidation, glutathione peroxidase and superoxide dismutase activity, thus this agent seems to be a valuable tool as it merely leads to glutathione depletion (Mehmetcik et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Effect of dimethylmaleate and phorone on glutathione content of Setaria cervi (Nematoda: Filarioidea) during in vitro incubation

2007

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SummaryGlutathione metabolism represents a prospective target for antifilarial drug design, and therefore, the alterations in glutathione (GSH) content of filarial worms by known mammalian GSH depletors i.e. dimethylmaleate (DMM) and phorone were first thought for investigation in model filarial worms Setaria cervi. The dose dependent GSH depletion was achieved when these worms were incubated at 37°C for 6 h in Hanks balanced salt solution with varying concentrations (10 -250 µM) of DMM or phorone. During the short incubation period of 6 h, 250 µM of DMM and phorone declined more than 90 % of the GSH content of filarial worms.

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“…Under these conditions, the hepatic content of glutathione as measured by the method od Sedlack & Lindsay (1968) valued 0.39&0.09 pmol/g as compared to 7.45k0.66 pmol/g in control rats (meanskS.E.M., n = 8 each). Phorone has been previously shown not to influence microsomal enzyme activities which are responsible for halothane bioactivation (Younes et al 1986). In the respective experiments, deferrioxamine (500 mg/kg in 10 ml/kg 0,9% NaCl solution intraperitoneally) diethyldithiocarbamate or (+)-catechin (200 mg/kg in 10 ml/kg 1 % carboxymethylcellulose solution orally each) were administered 30 min.…”

Section: Methodsmentioning

confidence: 99%

Enhanced in Vivo‐Lipid Peroxidation Associated with Halothane Hepatotoxicity in Rats

Younes¹,

Heger²,

Wilhelm³

et al. 1988

Pharmacology & Toxicology

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To study the role of lipid peroxidation in halothane-induced hepatic damage, ethane exhalation by rats exposed to 1% halothane for 1 hour was determined under normoxic (21% O2) and hypoxic (6% O2) conditions. The effects of microsomal enzyme induction by phenobarbital and/or glutathione depletion on this parameter of in vivo lipid peroxidation were studied. To assess the degree of liver damage, serum activities of liver specific enzymes (glutamate-pyruvate-transaminase, GPT, and sorbitol dehydrogenase, SDH) were measured 3 hrs after the end of exposure. Besides, liver content of thiobarbituric acid-reactive material was estimated as a further parameter of lipid peroxidation. Enhanced rates of lipid peroxidation over basal levels were only seen under conditions leading to hepatic damage, i.e. phenobarbital induction and hypoxia. The highest rate of lipid peroxidation was observed after depletion of hepatic glutathione in addition to microsomal enzyme induction and hypoxia. Deferrioxamine, diethyldithiocarbamate and (+)-catechin inhibited in vivo lipid peroxidation, but only (+)-catechin suppressed halothane-hepatoxicity. These results indicate that halothane-induced hepatic damage is associated with an enhanced rate of lipid peroxidation, but this might not be the only mechanism of halothane toxicity.

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Glutathione Depletion by Phorone Organ Specificity and Effect on Hepatic Microsomal Mixed-Function Oxidase System

Cited by 22 publications

References 16 publications

Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases

Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases

Effect of dimethylmaleate and phorone on glutathione content of Setaria cervi (Nematoda: Filarioidea) during in vitro incubation

Enhanced in Vivo‐Lipid Peroxidation Associated with Halothane Hepatotoxicity in Rats

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