Pretreatment with BSO, an inhibitor of GSH synthesis, ..
The role of glutathione (GSH) in protecting plants from chilling injury was analyzed in seedlings of a chilling-tolerant maize (Zea mays L.) genotype using buthionine sulfoximine (BSO), a specific inhibitor of γ-glutamylcysteine (γEC) synthetase, the first enzyme of GSH synthesis. At 25 °C, 1 mM BSO significantly increased cysteine and reduced GSH content and GSH reductase (GR: EC 126.96.36.199) activity, but interestingly affected neither fresh weight nor dry weight nor relative injury. Application of BSO up to 1 mM during chilling at 5 °C reduced the fresh and dry weights of shoots and roots and increased relative injury from 10 to almost 40%. Buthionine sulfoximine also induced a decrease in GR activity of 90 and 40% in roots and shoots, respectively. Addition of GSH or γEC together with BSO to the nutrient solution protected the seedlings from the BSO effect by increasing the levels of GSH and GR activity in roots and shoots. During chilling, the level of abscisic acid increased both in controls and BSO-treated seedlings and decreased after chilling in roots and shoots of the controls and in the roots of BSO-treated seedlings, but increased in their shoots. Taken together, our results show that BSO did not reduce chilling tolerance of the maize genotype analyzed by inhibiting abscisic acid accumulation but by establishing a low level of GSH, which also induced a decrease in GR activity.
(BSO) is an inhibitor of GSH ..
We demonstrated that the GSH synthesis inhibitor buthionine sulfoximine (BSO) synergistically enhanced L-PAM activity (inducing 2–4 logs of cell kill) against nine MM cell lines (also in the presence of marrow stroma or cytokines) and in seven primary MM samples (combination indices
AB - Lipoxygenase metabolites of arachidonic acid have been proposed as possible mediators of hypoxic pulmonary vasoconstriction (HPV) in the rat. Since reduced glutathione (GSH) is a required substrate for the synthesis of the sulfidopeptide eicosanoid leukotriene C4 (LTC4), we reasoned that this specific GSH dependence of LTC4 synthesis might allow us to distinguish between the roles of sulfidopeptide leukotrienes and other 5-lipoxygenase metabolites of arachidonic acid. In the present study we have examined the effect of in vivo pretreatment with the GSH synthesis inhibitor buthionine sulfoximine (BSO) on both the hypoxic pressor response and lung leukotriene synthesis in the rat. The intraperitoneal administration of 4 mmol/kg of BSO 30, 20, and 4 h prior to lung excision significantly depleted total lung glutathione as compared to saline-pretreated controls. This depletion of glutathione was associated with a significant attenuation of HPV in isolated perfused lungs but no alteration in pressor responses to angiotensin II or KCl. In addition, hypoxia-associated LTC4 levels in lung homogenates were significantly lower in animals pretreated with BSO than in saline-pretreated controls. The specificity of the effects of BSO on lung leukotriene synthesis was examined by quantitating immunoreactive leukotrienes produced by unstimulated and ionophore A23187-stimulated parenchymal lung fragments. Ionophore stimulation of lung fragments from BSO-preatreated rats produced 76 ± 12.2% as much LTC4 and 127 ± 22.3% as much leukotriene B4 as did fragments from saline-pretreated rats. Our data demonstrating that GSH depletion caused parallel reductions in both HPV and hypoxia-associated lung LTC4 levels are therefore consistent with the hypothesis that sulfidopeptide leukotrienes are involved in this pressor response in the rat.
(BSO), an inhibitor of GSH synthesis
N2 - TNF is a major mediator in the pathogenesis of endotoxic shock, and its inhibition has a protective effect in various animal models of sepsis or endotoxin (lipopolysaccharide, LPS) toxicity. LPS treatment also induces an oxidative damage mediated by increased production of reactive oxygen intermediates. N-Acetylcysteine (NAC) is an antioxidant and a precursor of the synthesis of glutathione (GSH) and was reported to protect against LPS toxicity and LPS-induced pulmonary edema. In this study we investigated the effect of NAC on TNF production and LPS lethality in mice. The results indicated that oral administration of NAC protects against LPS toxicity and inhibits the increase in serum TNF levels in LPS-treated mice. The inhibition was not confined to the released form of TNF, since NAC also inhibited LPS-induced spleen-associated TNF. On the other hand, the inhibitor of GSH synthesis, dl-buthionine-(SR)-sulfoximine (BSO), had the opposite effect of potentiating LPS-induced TNF production, and this was associated with a decrease in liver GSH levels. Repletion of liver GSH with NAC reversed this effect. NAC was also active in inhibiting TNF production and hepatotoxicity in mice treated with LPS in association with a sensitizing dose of Actinomycin D. These data indicate that GSH can be an endogenous modulator of TNF production in vivo. On the other hand, NAC pretreatment did not inhibit other effects of LPS, particularly induction of serum IL-6, spleen IL-1α, and corticosterone, in the same experimental model, suggesting that the observed effect could be specific for TNF.
BSO) is an inhibitor of GSH synthesis
N2 - A potential mechanism of hearing loss due to acoustic overstimulation is the generation of reactive oxygen species (ROS). ROS not removed by antioxidant defenses could be expected to cause significant damage to the sensory cells of the cochlea. We studied the influence of the antioxidant glutathione (GSH) on noise-induced hearing loss by using L-buthionine-[S,R]- sulfoximine (BSO), an inhibitor of GSH synthesis, and 2-oxothiazolidine-4- carboxylate (OTC), a cysteine prodrug, which promotes rapid restoration of GSH when GSH is acutely depleted. Pigmented female guinea pigs were exposed to broadband noise (102 dB SPL, 3 h/day, 5 days) while receiving daily injections of BSO, OTC, or saline. By weeks 2 and 3 after noise exposure, BSO-treated animals showed significantly greater threshold shifts above 12 kHz than saline-treated subjects, whereas OTC-treated animals showed significantly smaller threshold shifts at 12 kHz than controls. Histologically assessed noise-induced damage to the organ of Corti, predominantly basal turn row 1 outer hair cells, was most pronounced in BSO- treated animals. High performance liquid chromatographic analysis showed that OTC significantly increased cysteine levels, but not GSH levels, in the cochlea. These findings show that GSH inhibition increases the susceptibility of the cochlea to noise-induced damage and that replenishing GSH, presumably by enhancing availability of cysteine, attenuates noise-induced cochlear damage.