Hepatotoxic effect of cyclosporin A in the mitochondrial respiratory chain.
Cyclosporin A (CyA), a potent immunosuppressant, was used to determine the hepatotoxic effect in long-term treatments. Male Wistar rats were used in these experiments. They were given CyA chronically at doses used in patients for 120 days, and at doses of 5, 10, 15 and 20 mg kg(-1) day(-1). These doses amount to CyA values in blood of 200 +/- 24, 314 +/- 40, 445 +/- 33 and 598 +/- 53 ng ml(-1), respectively. A significant increase in glutamate dehydrogenase (GLDH) was found in the groups treated with 15 and 20 mg kg(-1) day(-1), which would point to mitochondria as the potential target of the toxic action of CyA. The mitochondrial respiratory chain of rat livers was studied in enzyme complexes I and II. Enzyme complex I was determined by spectrophotometry at 340 nm using NADH oxidase with the respirable substrate 10 mm NADH; enzyme complex II was determined by monitoring succinate dehydrogenase by oxymetry using the respirable substrate 10 mm succinate. The results show the inhibition of NADH oxidase in the groups treated with 10, 15 and 20 mg kg(-1) day(-1), an effect dependent both on time and on CyA concentration. Enzyme complex II showed a decrease in oxygen consumption. These findings were confirmed by histological studies (hematoxylin-eosin technique).


CONCLUSIONS
Long-term treatment with CyA at doses of 15 and 20 mg kg(-1) day(-1), amounting to concentrations in blood of 445 +/- 33 and 598 +/- 53 ng ml(-1), causes alterations in the mitochondria, revealed by the increase in serum GLDH and by the functional alteration of enzyme complexes I and II of the mitochondrial respiratory chain.
Rodríguez
Lilia Cristina De la Cruz
LC
Instituto de Bioquímica Aplicada, Facultad de Bioquímica, Química y Farmacia-Universidad Nacional de Tucumán, Balcarce 747, (4000), San Miguel de Tucumán, Argentina. vicedecanato@fbqf.unt.edu.ar
Araujo
Carmen Rosa
CR
Posleman
Sara Emilia
SE
Rey
María del Rosario
Mdel R
D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D016572:Cyclosporine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000378:metabolism*; D042963:Electron Transport Complex II / Q000378:metabolism*; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D007166:Immunosuppressive Agents; D009097:Multienzyme Complexes; C478189:respiratory complex II; D016572:Cyclosporine; D042963:Electron Transport Complex II; D005969:Glutamate Dehydrogenase; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D001219:Aspartate Aminotransferases; D042967:Electron Transport Complex I