Lipid peroxidation in presence of ebselen.
ABSTRACT Lipid peroxidation is initiated by cell damage. After homogenisation of porcine heart tissue in aqueous solution we observed the same lipid peroxidation products as detected after heart infarction. We used this observation to study the influence of ebselen (2-phenyl-1,2-benzoisoselenazol-3-(2H)-one) on the generation of oxidatively derived monohydroxy fatty acids and alpha-hydroxyaldehydes, typical lipid peroxidation (LPO) products. Heart tissue was homogenised before and after enzyme destruction and with addition of ebselen. The obtained LPO products were analysed by GC/MS after appropriate derivatisation and quantified by using internal standards. The amount of monohydroxy fatty acids and alpha-hydroxyaldehydes increased considerably in the porcine heart homogenates in which the enzymes were kept active. Addition of ebselen caused an additional significant increase of hydroxy fatty acids, while the increase of aldehydic compounds was less. These results confirm the glutathione peroxidase-like activity of ebselen but demonstrate also that it does not prevent lipid peroxidation.
Article: Multifunctional Ebselen drug functions through the activation of DNA damage response and alterations in nuclear proteins.[show abstract] [hide abstract]
ABSTRACT: Several studies have demonstrated that Ebselen is an anti-inflammatory and anti-oxidative agent. Contrary to this, studies have also shown a high degree of cellular toxicity associated with Ebselen usage, the underlying mechanism of which remains less understood. In this study we have attempted to identify a possible molecular mechanism behind the above by investigating the effects of Ebselen on Saccharomyces cerevisiae. Significant growth arrest was documented in yeast cells exposed to Ebselen similar to that seen in presence of DNA damaging agents (including methyl methane sulfonate [MMS] and hydroxy urea [HU]). Furthermore, mutations in specific lysine residues in the histone H3 tail (H3 K56R) resulted in increased sensitivity of yeast cells to Ebselen presumably due to alterations in post-translational modifications of histone proteins towards regulating replication and DNA damage repair. Our findings suggest that Ebselen functions through activation of DNA damage response, alterations in histone modifications, activation of checkpoint kinase pathway and derepression of ribonucleotide reductases (DNA repair genes) which to the best of our knowledge is being reported for the first time. Interestingly subsequent to Ebselen exposure there were changes in global yeast protein expression and specific histone modifications, identification of which is expected to reveal a fundamental cellular mechanism underlying the action of Ebselen. Taken together these observations will help to redesign Ebselen-based therapy in clinical trials.Biochemical pharmacology 01/2012; 83(2):296-303. · 4.25 Impact Factor