Glutathione Synthesis
Robert A. Greenwald in CRC Handbook of Methods for Oxygen Radical Research, 2018
A satisfactory approach to the production of glutathione deficiency consists of inhibiting γ-glutamylcysteine synthetase. Such inhibition can be produced by buthionine sulfoximine.25-29 Although methionine sulfoximine inhibits γ-glutamylcysteine synthetase,17 this compound also inhibits glutamine synthetase and therefore produces convulsions.30-33 Replacement of the methyl group of methionine sulfoximine by the more bulky n-butyl moiety leads to a compound that does not interact with glutamine synthetase. Thus, mice treated with buthionine sulfoximine do not experience convulsions.26 After treatment with buthionine sulfoximine, the glutathione levels of the liver, kidney, plasma, pancreas, and muscle decline rapidly.27 The turnover of glutathione in these tissues is sufficiently rapid so that depletion occurs within a short period of time. The rate of decline of the level of glutathione in tissues reflects its rate of utilization, which is about equal to its rate of transport from the cells. The decrease in the plasma glutathione level after treatment with buthionine sulfoximine reflects the substantial interorgan transport of glutathione. Plasma glutathione is derived mainly from the liver and, therefore, after inhibition of glutathione synthesis in the liver, the plasma level falls. Buthionine sulfoximine has been successfully used to deplete the glutathione levels of cells grown in tissue culture.29
Mechanisms of Resistance to Antineoplastic Drugs
Robert I. Glazer in Developments in Cancer Chemotherapy, 2019
Although increased GSH pools have been reported in cells resistant to phenylalanine mustard, the relationship between this increase and the development of resistance is not clear. However, this finding is of potential therapeutic interest as it is now possible to manipulate levels of this tripeptide in vivo. Indeed, buthionine sulfoximine (BSO) has been shown to be a selective inhibitor of γ-glutamyl cysteine synthetase and has proven effective in inhibiting GSH synthesis and lowering intracellular GSH pools. Moreover, BSO has recently been used to reduce GSH levels in phenylalanine mustard-resistant L1210 cells.49,74 Under these conditions of decreased GSH levels, the sensitivity of resistant cells to the alkylating agent increased. Similarly, BSO has been shown to potentiate phenylalanine mustard toxicity in drug-resistant human ovarian cancer cells, both in vitro and in tumor-bearing mice.75 The clinical utility of BSO in potentiating the cytotoxicity of certain antineoplastic agents, as well as the use of esters of GSH as protecting or rescue agents, is currently being assessed.76
The Use of Brain Slices in the Study of Free Radical Actions
Avital Schurr, Benjamin M. Rigor in BRAIN SLICES in BASIC and CLINICAL RESEARCH, 2020
To test the contribution of glutathione to peroxide-induced free radical damage and repair in the hippocampal slice preparation, GSH was depleted. Treatment with buthionine sulfoximine (BSO) irreversibly inhibits the synthesis of GSH,95,96 while diamide or dimethylfumarate inactivates the tripeptide through oxidation or covalent bonding, respectively.100,101 Pretreatment of hippocampal slices with BSO for 2 h and subsequent incubation with DMF reduces glutathione levels to 4.2% of control.91 Depletion of glutathione does not alter the magnitude of the electrophysiological effects of peroxide on synaptic efficacy or E/S coupling, but the changes become irreversible (Figure 6). Glutathione is required for repair of free radical damage in hippocampal slices.
Bioactivation of herbal constituents: mechanisms and toxicological relevance
Published in Drug Metabolism Reviews, 2019
Luteolin (3′,4′,5,7-tetrahydroxyflavone, Figure 11(g)), a well-known flavonoid present in many diets, supplements and herbal medicines, possesses a variety of pharmacological activities including antioxidant, anti-inflammatory, antipruritic, antimicrobial, antitumor and neuroprotection effects (Seelinger et al. 2008). As a close analog of quercetin, luteolin is oxidized by CYP3A to an electrophilic ortho-benzoquinone intermediate that can be trapped by GSH (Shi et al. 2015) (Figure 11g). Induction of CYP3A by dexamethasone enhanced luteolin-induced cytotoxicity in primary hepatocytes, whereas inhibition of CYP3A by ketoconazole inhibited formation of luteolin GSH adducts and decreased the cytotoxicity (Shi et al. 2015). Depletion of intracellular GSH by L-buthionine sulfoximine (BSO) significant enhanced the cytotoxicity. These data suggested that CYP3A-mediated ortho-benzoquinone formation followed by GSH depletion is a molecular initiating event in luteotin-induced cytotoxicity. Meantime, it is conceivable that the ortho-benzoquinone intermediate of luteolin plays a critical role in its broad pharmacological activities such as antioxidant and anticancer effects (Kang et al. 2019).
An update on calcium carbonate nanoparticles as cancer drug/gene delivery system
Published in Expert Opinion on Drug Delivery, 2019
Solmaz Maleki Dizaj, Simin Sharifi, Elham Ahmadian, Aziz Eftekhari, Khosro Adibkia, Farzaneh Lotfipour
Multiple drug resistance (MDR) is a common disturbance in cancer treatment. Wu et al. designed a nanostructured system for the simultaneous delivery of MDR inhibitors with functional targeting activity and pH sensitivity. A polymer/inorganic hybrid nanoparticle was used as a carrier to co-load buthionine sulfoximine (BSO) (a glutathione synthesis inhibitor) and celecoxib which down-regulates p-glycoprotein (p-gp) expression that is involved in MDR. The synthesized delivery system was nominated as BSO/celecoxib@biotin-heparin/heparin/calcium carbonate/calcium phosphate nanoparticles (BSO/CXB@BNP). Pretreatment of drug-resistant cells (MCF-7/ADR) with BSO/CXB@BNP could successfully reverse MDR via down-regulation of glutathione and p-gp since BSO and CXB had synergistic effects in their inhibitory activities. Furthermore, BSO/CXB@BNP had a more strong impact on the reduction of MDR when compared with mono-inhibitor loaded nanoparticles (each of the chemicals (BSO or CXB) individually). In this regard, implementation of nano-carriers to deliver drug resistance inhibitors increases cellular uptake and accumulation of the inhibitors which in turn effectually reverses MDR [62].
Oxidative stress impairs cGMP-dependent protein kinase activation and vasodilator-stimulated phosphoprotein serine-phosphorylation
Published in Clinical and Experimental Hypertension, 2019
Anees A. Banday, Mustafa F. Lokhandwala
Reduced vasodilation in response to endothelium-dependent vasodilators such as acetylcholine is a hallmark of endothelial dysfunction and development of hypertension (2,3). The mechanisms underlying endothelial dysfunction are likely to be multifactorial but could be due to NO degradation or defective NO signaling caused, at least in part, by oxidative stress (2,3). Previously we have shown that rats treated with L-buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, exhibited oxidative stress and increased blood pressure (17). The blood vessels from these rats showed decreased response to acetylcholine and sodium nitroprusside (SNP) (17). The reduced response to acetylcholine in hypertensive animals has been extensively studied and could be explained by a decreased bioavailability of NO, partly due to its inactivation by oxidative stress. However, the diminished response to SNP remains unknown. Therefore, the present studies were carried out in endothelium-denuded mesenteric tissue to unravel the mechanisms for oxidative stress-mediated attenuation of NO signaling (independent of NO bioavailability) in smooth muscles which could be an important contributor to the development of hypertension. Since PKG is a primary determinant of NO-mediated vasorelaxation, the present study was designed to investigate the effect of oxidative stress on PKG signaling. SD rats were treated with BSO for 3 weeks and endothelial denuded blood vessels were used to study the impairment in NO/PKG/VASP pathway in the setting of hypertension.
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