title: Gamma-Glutamylcysteine Ethyl Ester Protects against Cyclophosphamide-Induced Liver Injury and Hematologic Alterations via Upregulation of PPARγand Attenuation of Oxidative Stress, Inflammation, and Apoptosis.
abstract: Gamma-glutamylcysteine ethyl ester (GCEE) is a precursor of glutathione (GSH) with promising hepatoprotective effects. This investigation aimed to evaluate the hepatoprotective effects of GCEE against cyclophosphamide- (CP-) induced toxicity, pointing to the possible role of peroxisome proliferator activated receptor gamma (PPARγ). Wistar rats were given GCEE two weeks prior to CP. Five days after CP administration, animals were sacrificed and samples were collected. Pretreatment with GCEE significantly alleviated CP-induced liver injury by reducing serum aminotransferases, increasing albumin, and preventing histopathological and hematological alterations. GCEE suppressed lipid peroxidation and nitric oxide production and restored GSH and enzymatic antioxidants in the liver, which were associated with downregulation of COX-2, iNOS, and NF-κB. In addition, CP administration significantly increased serum proinflammatory cytokines and the expression of liver caspase-3 and BAX, an effect that was reversed by GCEE. CP-induced rats showed significant downregulation of PPARγwhich was markedly upregulated by GCEE treatment. These data demonstrated that pretreatment with GCEE protected against CP-induced hepatotoxicity, possibly by activating PPARγ, preventing GSH depletion, and attenuating oxidative stress, inflammation, and apoptosis. Our findings point to the role of PPARγand suggest that GCEE might be a promising agent for the prevention of CP-induced liver injury.
authors.affiliation: College of Medicine, King Saud bin Abdulaziz University for Health Science (KSAU-HS), Riyadh, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.
authors.forename: Sultan
authors.initials: S
authors.lastname: Alqahtani
authors.affiliation: Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt.
authors.forename: Ayman M
authors.identifier: 0000-0003-0279-6500
authors.initials: AM
authors.lastname: Mahmoud
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D001772:Blood Cell Count; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000517:prevention & control; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003520:Cyclophosphamide / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D004151:Dipeptides; D016328:NF-kappa B; D047495:PPAR gamma; D051028:bcl-2-Associated X Protein; D008315:Malondialdehyde; D003520:Cyclophosphamide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D053148:Caspase 3; D005978:Glutathione; C017341:gamma-glutamylcysteine