Toxicity of the immune suppressant cyclosporin A in the rat

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Abstract
Cyclosporin A (Cy A) administered orally (100 mg/kg/24 hr) to adult Sprague‐Dawley rats for 21 days caused a number of functional and structural changes. Behavioural effects, including fits, were also observed during the first week. Two animals (25 per cent.) died on days 6 and 10 respectively; a third was killed on day 7 because of fits. Hair loss was continuous during the experimental period. There were marked decreases in total serum protein, albumin and aspartate aminotransferase, accompanied by rises in alkaline phosphatase and total bilirubin. Examination of the liver revealed moderate centrilobular fatty change and minor dilatation of endoplasmic reticulum. Impaired renal function was also evident from increases in serum urea and creatinine and a striking rise in urinary N‐acetyl‐β‐D‐glucos‐aminidase activity. Kidneys examined at 21 days showed focal proximal tubular cell (PTC) vacuolation and necrosis, clearly evident on light microscopy. Ultrastructural studies revealed dilatation and vesiculation of the smooth endoplasmic reticulum within PTC, together with increased lysosome production and the formation of myeloid figures. Glomeruli and distal tubular cells were unaffected.Cy A caused marked lymphopenia, with a progressive increase in circulating neutrophils and monocytes. This was accompanied by the appearance of atypical mononuclear cells in the peripheral blood. The cellularity of the bone marrow was significantly reduced. In the thymus, there was very marked depletion of the medullary zones, and histiocytes containing cellular debris appeared throughout. The most striking feature in the spleen was the loss of lymphocytes within the periarteriolar sheaths and marginal zones.