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The time course of contrast media (CM)-induced renal proximal tubular vacuolation was investigated in rats by light microscopy, transmission electron microscopy (TEM), and ultrastructural histochemistry for acid phosphate activity. Young adult male rats were treated with a single dose of 3.0 g I/kg Iotrolan (Isovist 300 mg I/ml) and sacrificed at 0 min, 5-min, 15-min, 15-min, 2-hr, and 24-hr intervals. Light microscopy of vibratome sections of freshly excised tissue of cryostat and paraffin sections was also performed to allow comparison of the appearance of the vacuoles in the fresh state with light and electron microscopy. The sequence of events seen to occur can be summarized as follows. CM-induced vacuolation occurred at a low level a soon as 5 min after compound administration. The vacuolation was observed by TEM but could not be detected by light microscopy. This was followed by an increase in size and numbers of vacuoles up to the 24-hr timepoint with a sequential increase in the staining for acid phosphatase activity of the vacuoles, most marked at the 24-hr timepoint. At timepoints less than 24 hr there appeared to be no marked increased in the normal complement by lysosomes or in the components of the Golgi-endoplasmic reticulum-lysosome pathway. At 24 hr, the vast majority, but not all, of the CM-induced vacuoles were positive for acid phosphatase activity. The intensity of staining varied, and there was evidence of infusion of small lysosomes with CM-induced vacuoles. These results suggest that formation of CM-induced vacuoles is a 2-stage process, following a normal pathway for the handling of endogenous and exogenous substances.

1. We investigated the biological activity of the difluoro analogue (WIN 36117) of ciprofibrate, a potent peroxisome proliferator, and re-examined the relative activity of clofibric acid and its 4-fluoro analogue (fluorofibric acid) in the rat. 2. Twenty-four hours after a single dose, ciprofibrate and WIN 36117 produced dosage-related reductions in plasma cholesterol (16-42 and 9-34% respectively) and triglycerides (14-32 and 9-22% respectively). However, a single dose of clofibric acid or fluorofibric acid produced hypocholesterolaemia only (32-58 and 9-29% reductions respectively). 3. After treatment for 7 days reductions in cholesterol were similar at all dosages of ciprofibrate (45% reduction, mean across groups) whereas the effects of WIN 36117, clofibric acid and fluorofibric acid were still dosage related (reductions of 21-44, 37-43 and 2-28% respectively). Hypotriglyceridaemia was produced by all compounds (ciprofibrate 36-50%, WIN 36117 14-36%, clofibric acid 18-48%, fluorofibric acid 6-28%). 4. After treatment for 14 days all compounds produced dosage-related decreases in plasma fibrinogen (ciprofibrate 18-33%, WIN 36117 7-11%, clofibric acid 13-26%, fluorofibric acid 7-15%). 5. Peroxisomal beta-oxidation activity was increased by WIN 36117 (4.8-fold) and fluorofibric acid (4.2-fold) although these increases were less than those produced by ciprofibrate (13.6-fold) and clofibric acid (7.0-fold). WIN 36117 and fluorofibric acid also produced smaller increases in peroxisome numbers, liver weight, and carnitine acetyl transferase activity and smaller decreases in glutathione S-transferase and glutathione peroxidase activities. 6. Maximal increases in peroxisomal beta-oxidation activity produced in cultured rat hepatocytes by WIN 36117 and fluorofibric acid were 58 and 72% of those produced by ciprofibrate and clofibric acid respectively. 7. These results indicate the difluoro and 4-fluoro analogues of ciprofibrate and clofibric acid are hypolipidaemic agents and peroxisome proliferators but with reduced potencies relative to the parent molecules.

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