The covalent binding of cyclosporin A to rat liver macromolecules in vivo and in vitro: the role of cytochrome P-450.
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.
Division of Toxicology, University of Leiden, The Netherlands.
J F
JF
Nagelkerke
R B
RB
Tijdens
E P
EP
Schwarz
M F
MF
Winters
L C
LC
Paul
G J
GJ
Mulder
D000818:Animals; D002478:Cells, Cultured; D003524:Cyclosporins / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007700:Kinetics; D046911:Macromolecular Substances / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D003524:Cyclosporins; D046911:Macromolecular Substances; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D010634:Phenobarbital