Simultaneous Inhibition of Renal Phospholipase A₂ and Glutathione Synthesis by Manoalide and <i>DL</i>-Buthionine Sulfoximine Induces Acute Tubular Dysfunction in Rats

Abstract

We have previously demonstrated that gentamicin-induced acute renal failure is mediated by the consumption of renal glutathione (GSH) and accumulation of oxidized phospholipids in tubular epithelial cells as a result of inhibition of phospholipase A₂ (PLA₂) activity. Based on these results, we tested the hypothesis that the simultaneous inhibition of PLA₂ and GSH synthesis induces acute renal failure similar in characteristics to gentamicin-induced acute renal failure. Male Sprague-Dawley rats kept under standard laboratory conditions were administered 3 mmol/kg of DL-buthionine sulfoximine (BSO; γ-glutamylcysteine synthetase inhibitor) and 30 μg/kg of manoalide (PLA₂ inhibitor), following which significant elevations in serum creatinine and urinary lysosomal enzyme levels (elevation of N-acetyl-β-D-glucosaminidase activity) were observed. The renal tissue GSH content was reduced in the group that received both BSO and manoalide as compared with the group that received manoalide alone. The renal tissue GSH content was also reduced in the group that received BSO alone. The renal tissue concentration of 2-thiobarbituric-acid-reactive substances increased rapidly, followed by an increase in renal tissue total phospholipid concentration in the group that received both BSO and manoalide. In contrast, the activity of PLA₂ in renal tissue decreased in the group that received both BSO and manoalide as compared with the groups that received BSO alone or physiological saline. In conclusion, concomitant administration of BSO and manoalide induces renal tubular damage and acute renal failure in rats, similar in characteristics to gentamicin-induced nephrotoxicity, whereas administration of BSO or manoalide alone did not. These results suggest that both inhibition of PLA₂ and GSH depletion are necessary for the induction of acute renal failure.

Effects of Glutathione Depletion on Hypoxia-induced Erythropoietin Production in Rats

“…Thus, we need to examine whether ROS acts as a key modulator in hypoxia-mediated EPO production in vivo. BSO employed in this experiment has been proven to inhibit glutamyl-cysteine synthetase, a rate-limiting step enzyme of GSH synthesis, resulting in the reduction of GSH contents in various tissues such as liver, lung, and kidney (Griffith and Meister, 1979;Kramer et al, 1985;Soejima et al, 2000). Because GSH acts to scavenge ROS as well as to regenerate other antioxidants, BSO treatment might lead the changes in cellular redox balance (Ganafa et al, 2002).…”

Evaluation of cefquinome's efficacy in controlling avian colibacillosis and detection of its residues using high performance liquid chromatography (HPLC)

“…Treatment with cefquinome improve the antioxidant levels as according to ( Soejima et al, 2000 ). Cephalosporins reduce hepatic oxidative damage, as they are thioether having free radical scavenging properties by preventing the free radical-mediated oxidation of sulfhydryl group.…”

“…Cefquinome is resistant to inactivation by β-lactamases due to addition of a methoxyimino-aminothiazolyl moiety into the acyl side chain which improve its antimicrobial potency and extensive antibacterial spectrum ( Marshall and Blair, 1999 , Neu, 1982 ). Fourth generation has free radical scavenging potential and good stability against enzymatic hydrolysis ( Soejima et al, 2000 ). Cephalosporins protect against hypochlorous acid (HOCl) oxidative damage.…”

Effect of cefepime on hematological, immunological and oxidant/antioxidant parameters in rats experimentally infected with E. coli ATCC 25922

“…The treatment with CFPM alone insignificantly affected the hepatic MDA level, SOD, CAT activities and GSH level, although treatment with cefepime in E.coli +CFPM group induced a significant reduction in the hepatic MDA, whilst hepatic SOD, CAT, and GSH were significantly increased PT. According to Soejima et al [44] cephalosporins as cefepime are thioether had free radical scavenging potential and effective in preventing the free radical-mediated oxidation of sulfhydryl group resulted in reduce hepatic oxidative damage.…”