The effect of immunosuppressive agents (FK-506, rapamycin) on renal P450 systems in rat models

It is well known that cyclosporin, rapamycin and FK-506 (tacrolimus) are me tabolized by the liver microsomal cytochrome P450 enzyme system. Although t here have been reports of interaction between these drugs and the renal P45 0 enzyme system, differences among these immunosuppressants has not been co mprehensively demonstrated. We have studied the individual capacities of th ese immunosuppressants to induce renal microsomal P450 enzymes similar to C YP2B4 and CYP4A2 by examining renal function in treated rats, and have corr elated the results by means of biochemical, immunological and immunohistoch emical assays of renal P450 enzymes. Cyclosporin caused impairment of renal function with an increase in renal-s pecific P450 content, but FK-506 and rapamycin did not. Laurate omega- and (omega-1)-hydroxylase activity increased in rats treated with rapamycin but decreased in those treated with FK-506. Prostaglandin A(1) (PGA(1)) omega- hydroxylase activity increased in rats treated with FK-506 but was reduced by treatment with cyclosporin. Aminopyrine N-demethylase activity increased in rats treated with cyclosporin or FK-506, but not in those treated with rapamycin. Western-blot analysis revealed significant induction of P450, (s imilar to CYP2B4 of the rabbit P450 isozyme) in kidneys from rats treated w ith cyclosporin but not in those from rats receiving FK-506 or rapamycin. H istochemical studies clearly demonstrated a form of P450 such as CYP4A2 in the proximal tubules of rats treated with cyclosporin, but not in those of rats treated with FK-506 or rapamycin. These results show that although cyclosporin has a strong effect on renal P 450 systems and induces such a system in kidney cortex (microsomal P450), F K-506 and rapamycin have no substantial effect on the induction of renal P4 50. These findings might clarify the nephrotoxicity induced by these immuno suppressive drugs.