In vitro investigations on the differential pro-oxidant and/or antioxidant properties of cyclosporin A and tacrolimus in human and rat liver microsomes.
OBJECTIVE
The use of cyclosporin A (CSA) and tacrolimus (TAC) in organ transplantation and in the therapy of immune disorders is often hampered by adverse effects, mainly nephro-, hepato- and neurotoxicity. For the development of these side effects, among others, an increased formation of reactive oxygen species, probably generated by the cytochrome P450 (CYP) system, has been accused. Since in this respect literature data are inconsistent, in the present study possible pro- and/or antioxidant effects of CSA and TAC and the involvement of the CYP system were re-evaluated in vitro.


METHODS
Effects of CSA and TAC were examined on CYP mediated oxidase functions by stimulated lipid peroxidation (LPO), H2O2 production, and lucigenin (LC) or luminol (LM) amplified chemiluminescence (CL) in liver microsomes of either untreated rats or of rats treated with beta-naphthoflavone (BNF), phenobarbital (PB) or dexamethasone (DEX) and in human liver microsomes.


RESULTS
In rat liver microsomes, CSA displayed pro-oxidant properties (though only very slightly), whereas in human liver microsomes small antioxidant effects were seen. With TAC in both species the antioxidant capacity prevailed. Treatment of rats with BNF or DEX caused an increase in the pro-oxidant effects of CSA with respect to LPO or LM-CL, whereas in liver microsomes of DEX-treated rats H2O2 production and LC-CL were diminished.


CONCLUSIONS
CSA seems to have both pro-oxidant and antioxidant properties, whereas with TAC mainly an antioxidant capacity was seen. The CYP system seems to be involved in the pro-oxidant influence of CSA. Whether pro-oxidant or antioxidant effects predominate may depend on the antioxidant capacity of a tissue and on the CYP isoforms mainly present.
Lupp
A
A
Institute of Pharmacology and Toxicology, Friedrich Schiller University, 07740 Jena, Germany. Amelie.Lupp@mti.uni-jena.de
Kuhn
U D
UD
Karge
E
E
Adam
G
G
Fleck
C
C
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver; D016877:Oxidants / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology*; D019324:beta-Naphthoflavone / Q000494:pharmacology
D000975:Antioxidants; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D016877:Oxidants; D019324:beta-Naphthoflavone; D003907:Dexamethasone; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D006861:Hydrogen Peroxide; D016559:Tacrolimus; D010634:Phenobarbital