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.
Nagelkerke
J F
JF
Division of Toxicology, University of Leiden, The Netherlands.
Tijdens
R B
RB
Schwarz
E P
EP
Winters
M F
MF
Paul
L C
LC
Mulder
G J
GJ
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