In vivo prevention of cyclophosphamide-induced Ca2+ dependent damage of rat heart and liver mitochondria by cyclosporin A.
The use of Cyclophosphamide, an anti-cancer and immunosuppressant drug, is accompanied by a number of side effects. Rats injected with a single dose of cyclophosphamide (200 mg kg-1 body weight) showed an increase in the levels of serum glutamate-oxaloacetate transaminase, serum glutamate-pyruvate transaminase, glucose-6-phosphate dehydrogenase and creatine phosphokinase isoenzyme by 53, 24, 55 and 135%, respectively. Also the ability of heart or liver mitochondria to retain accumulated Ca2+ and tetraphenylphosphonium ion was sharply affected in treated rats. Rats injected with the same dose of cyclophosphamide plus cyclosporin A (500 micrograms kg-1 body weight) showed reduction in the levels of those enzymes by about 44, 21, 43 and 57%, respectively compared to cyclophosphamide-treated rats. Cyclosporin A treatment also restored mitochondrial ability to retain accumulated Ca2+ and tetraphenyl phosphonium ions nearly to the level of untreated rats. We suggest that cyclophosphamide induced cardio and hepatotoxicity by increasing heart and liver inner mitochondrial membrane permeability to Ca2+. The protective effect of cyclosporin A against cyclophosphamide-induced damage also support this suggestion.
al-Nasser
I A
IA
Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000633:toxicity; D001219:Aspartate Aminotransferases / Q000097:blood; D002118:Calcium / Q000378:metabolism*; D003402:Creatine Kinase / Q000097:blood; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity*; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D005954:Glucosephosphate Dehydrogenase / Q000097:blood; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism*; D009861:Onium Compounds / Q000493:pharmacokinetics; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley