Abstract
Cyclosporine A is an immunosuppressive drug used after organ's transplantation. The adverse effects on such organs as kidney or liver may limit its use. Oxidative stress is proposed as one of the mechanisms of organs injury. The study was designed to elucidate CsA-induced changes in liver function, morphology, oxidative stress parameters, and mitochondria in rat's hepatocytes. Male Wistar rats were used: group A (control) receiving physiological saline, group B cyclosporine A in a dose of 15 mg/kg/day subcutaneously, and group C the CsA-vehicle (olive oil). On the 28th day rats were anesthetized. The following biochemical changes were observed in CsA-treated animals: increased levels of ALT, AST, and bilirubin in the serum, statistically significant changes in oxidative stress parameters, and lipid peroxidation products in the liver supernatants: MDA+4HAE, GSH, GSSG, caspase 3 activity, and ADP/ATP, NAD+/NADH, and NADP+/NADPH ratios. Microscopy of the liver revealed congestion, sinusoidal dilatation, and focal hepatocytes necrosis with mononuclear cell infiltration. Electron microscope revealed marked mitochondrial damage. Biochemical studies indicated that CsA treatment impairs liver function and triggers oxidative stress and redox imbalance in rats hepatocytes. Changes of oxidative stress markers parallel with mitochondrial damage suggest that these mechanisms play a crucial role in the course of CsA hepatotoxicity.
Highlights
Cyclosporine A (CsA) belongs to calcineurin inhibitors used in patients after kidney, liver, heart, lung, and heart-lung transplants for graft-versus-host disease (GVHD) prophylaxis [1, 2].CsA is used to treat the majority of autoimmune diseases [3], in dermatology to treat psoriasis, autoimmune dermatitis, or chronic idiopathic urticaria [4, 5].The major adverse side effect of CsA is acute and chronic nephrotoxicity.CsA can cause metabolic and electrolyte disorders, that is, weight gain, hyperglycaemia, hyperlipidaemia, hypercalcaemia, and hypomagnesaemia [6].Experimental studies and clinical observations reveal that CsA can lead to drug-induced liver injury (DILI)
CsA administration resulted in decreased liver function measured by serum levels of AST, ALT, and bilirubin when compared with the control group (Table 1)
In the present study assessing the effects of CsA on liver injury in animals, changes in liver function parameters, microscopic and ultrastructural lesions in the hepatocytes, and changes in oxidative stress parameters were analysed
Summary
Cyclosporine A (CsA) belongs to calcineurin inhibitors used in patients after kidney, liver, heart, lung, and heart-lung transplants for graft-versus-host disease (GVHD) prophylaxis [1, 2].CsA is used to treat the majority of autoimmune diseases [3], in dermatology to treat psoriasis, autoimmune dermatitis, or chronic idiopathic urticaria [4, 5].The major adverse side effect of CsA is acute and chronic nephrotoxicity.CsA can cause metabolic and electrolyte disorders, that is, weight gain, hyperglycaemia, hyperlipidaemia, hypercalcaemia, and hypomagnesaemia [6].Experimental studies and clinical observations reveal that CsA can lead to drug-induced liver injury (DILI). Cyclosporine A (CsA) belongs to calcineurin inhibitors used in patients after kidney, liver, heart, lung, and heart-lung transplants for graft-versus-host disease (GVHD) prophylaxis [1, 2]. CsA is used to treat the majority of autoimmune diseases [3], in dermatology to treat psoriasis, autoimmune dermatitis, or chronic idiopathic urticaria [4, 5]. The major adverse side effect of CsA is acute and chronic nephrotoxicity. Experimental studies and clinical observations reveal that CsA can lead to drug-induced liver injury (DILI). In CsAinduced liver injury, functional and morphological changes are observed. The functional changes include elevated serum levels of liver transaminases and alkaline phosphatase, cholestasis, hyperbilirubinemia, increased production of bile salts, and impaired secretion of lipids [7,8,9]
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