Stimulation of hepatic glutathione formation by administration of L-2-oxothiazolidine-4-carboxylate, a 5-oxo-L-prolinase substrate.

Williamson, Joanne M.; Meister, Alton

doi:10.1073/pnas.78.2.936

Cited by 167 publications

(66 citation statements)

References 17 publications

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“…Previous studies have demonstrated that OTC is more effective than N-acetylcysteine in replenishing intracellular GSH stores (Williamson and Meister, 1981;Mesina et al, 1989) and blocks airway hyperresponsiveness and inflammation in an asthmatic animal model (Lee et al, 2004c). Consistent with previous observations, administration of OTC decreases airway inflammation.…”

Section: Discussionsupporting

confidence: 78%

An antioxidant modulates expression of receptor activator of NF-κB in asthma

Lee

Park²,

Park³

et al. 2006

Exp Mol Med

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Oxidative stress plays critical roles in airway inflammation that is usually accompanied by increased vascular permeability and plasma exudation. VEGF increases vascular permeability and leads to airway inflammation. In addition, VEGF has been shown to enhance receptor activator of NF-κB (RANK) expression in endothelial cells. An aim of the study was to determine the potential role of antioxidant in the regulation of RANK expression in murine model of asthma. We have used a C57BL/6 mouse model of allergic asthma to evaluate the effect of L-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine, which acts as an antioxidant, and VEGF receptor inhibitor on RANK mRNA expression. The mice develop the following pathophysiological features of asthma in the lungs: increased expression of RANK mRNA, increased number of inflammatory cells of the airways, increased vascular permeability, and increased levels of VEGF. Administration of OTC and VEGF receptor inhibitor markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs. We also showed that the increased RANK mRNA expression at 72 h after ovalbumin inhalation were reduced by the administration of OTC or VEGF receptor inhibitor. The results indicate that OTC and VEGF receptor inhibitor which inhibit up-regulation of VEGF expression modulate RANK expression that may be in association with the regulation of vascular permeability, and suggest that VEGF may regulate the RANK expression. These findings provide a crucial molecular mechanism for the potential use of antioxidants to prevent and/or treat asthma and other airway inflammatory disorders.

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Section: Discussionsupporting

confidence: 78%

An antioxidant modulates expression of receptor activator of NF-κB in asthma

Lee

Park²,

Park³

et al. 2006

Exp Mol Med

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“…specific inhibitor of glutathione synthesis, 42 or with OTC, 10 mg/day, which contributes to glutathione synthesis. 43,44 BSO treatment reduced MPM glutathione content by 22%, whereas OTC treatment increased cellular glutathione content by 26%, compared with control non-supplemented E 0 mice ( Figure 3A). In contrast, MPM lipid peroxide levels increased by 300% in BSO-treated E 0 mice, compared with control E 0 mice ( Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

Oxidative stress increases the expression of the angiotensin-II receptor type 1 in mouse peritoneal macrophages

Keidar

Heinrich

Kaplan

et al. 2002

J Renin Angiotensin Aldosterone Syst

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Angiotensin II (Ang II) has been shown to accelerate atherogenesis, and the cellular Ang II type 1 (AT 1 ) -receptor mediates most of Ang II-induced proatherogenic effects. In this study we have examined the effect of macrophage oxidative stress on cellular AT 1 -receptor expression.Mouse peritoneal macrophages (MPM) from apolipoprotein-E deficient (E 0 ) mice at increasing ages (1-6 months) demonstrated an age-dependent increase in cellular lipid-peroxides (PD) content. In parallel, the AT 1 -receptor mRNA and protein levels both increased by up to 3.7-fold and 1.7-fold, respectively, in MPM from 6-month old mice compared with 1-month old mice. Vitamin E supplementation to E 0 mice significantly decreased the MPM PD content and macrophage AT 1 -receptor mRNA expression compared with placebo-treated mice. The role of oxidative stress in the cellular expression of AT 1 -receptors was further demonstrated by manipulation of macrophage glutathione content. Buthionine-sulfoximine, a glutathione synthesis inhibitor, increased MPM PD content and AT 1 -receptor mRNA expression, whereas L-2-oxothiazolidine-4-carboxylic acid, that contributes to glutathione synthesis, reduced macrophage PD and AT 1 -receptor mRNA expression. Incubation of MPM with oxidised low-density lipoproteins (LDL) led to a significant, dose-dependent and time-dependent increase in macrophage AT 1 -receptor mRNA and protein expression, compared with control cells. In contrast, native LDL or acetylated LDL did not significantly affect macrophage AT 1 -receptor mRNA expression.In conclusion, our findings suggest that oxidative stress in macrophages induces AT 1 -receptor expression. This phenomenon can stimulate the interaction of Ang II with macrophages and hence accelerate macrophage foam cell formation and early atherogenesis.

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“…N ¼ number of subjects in the study; F ¼ female; M ¼ male; Rxo6week ¼ on antipsychotic medication within 6 weeks of death (only typical neuroleptics). Table 1 Continued N-acetylcysteine is used to target cystine-glutamate antiporters because it is a prodrug for cyst(e)ine (Williamson and Meister, 1981;Meister, 1985;Pileblad and Magnusson, 1992). However, cysteine can also be transported by the sodium-dependent glutamate transporter EAAC1 (Aoyama et al, 2006).…”

Section: N-acetylcysteine Attenuates Pcp-evoked Performance Deficits mentioning

confidence: 99%

Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Baker

Madayag

Kristiansen

et al. 2007

Neuropsychopharmacol

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Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine-glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine-glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by Nacetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystineglutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine-glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine-glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine-glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP.

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Stimulation of hepatic glutathione formation by administration of L-2-oxothiazolidine-4-carboxylate, a 5-oxo-L-prolinase substrate.

Cited by 167 publications

References 17 publications

An antioxidant modulates expression of receptor activator of NF-κB in asthma

An antioxidant modulates expression of receptor activator of NF-κB in asthma

Oxidative stress increases the expression of the angiotensin-II receptor type 1 in mouse peritoneal macrophages

Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

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