ABSTRACT
Incubation of rat liver S9 with [3H]cyclosporin A ([3H]CSA) resulted in covalent binding of CSA to macromolecules. Binding was dependent on the presence of NADPH and could be inhibited by SKF-525A. Incubation of isolated rat liver parenchymal cells with CSA resulted in a concentration-dependent binding which increased with incubation time for at least 2 h. Addition of SKF-525 A (0.5 mM) decreased the binding by 83% while viability of the cells was unchanged. Pretreatment of the cells with diethylmaleate doubled the binding of CSA, indicating that glutathione can prevent binding of CSA. When [3H]CSA was injected i.v. radioactivity was covalently bound to liver and kidney macromolecules. Induction of cytochrome P-450 by phenobarbital resulted in enhanced in vivo covalent binding in liver and kidney. Whether this covalent binding of CSA is related to its cytotoxicity is yet unclear.
