Effects of cyclosporine A on the rat liver and kidney protein pattern, and the influence of vitamin E and C coadministration.

Abstract

The effects of cyclosporine A (CsA), a potent immunosuppressive drug, were examined in rat liver and kidney samples using two-dimensional electrophoretic protein analysis. Of a total of 370 liver and 336 kidney spots analyzed, 8% (29 spots) and 6% (19 spots), respectively, showed a significant drug-induced change (p < 0.01), which was predominantly reflected in increased protein abundance (62% and 74% of the changes, respectively). Of the 48 proteins changed in either organ, 14 were most probably common to both tissues and one of these was significantly increased in both the liver and the kidney. Most of the other 13 showed similar trends (either increases or decreases) in both organs. However, the most striking drug effect seen in this study concerned an unidentified protein present only in the kidney, which completely disappeared upon CsA treatment. It was also investigated whether the drug-induced changes could be prevented by the coadministration of the radical scavengers vitamin E and C with CsA. Spots changed by the administration of the drug were classified according to three different categories, based on their response profiles in rats treated with CsA in combination with the vitamins: (i) spots which were changed by CsA as well as by CsA in combination with the vitamins (12 liver and 4 kidney spots), (ii) spots which were changed by CsA and showed an additional increase of this change by CsA plus the vitamins (no liver and 4 kidney spots), and (iii) spots which were changed by CsA but not by CsA in combination with the vitamins (8 liver and 6 kidney spots). These results showed that in both organs the vitamins were able to prevent around 30% of the effects caused by CsA, and that two-dimensional gel electrophoresis is an excellent tool to demonstrate such drug interactions at the molecular level.