Lupp A, Kuhn UD, Karge E, Adam G, Fleck C.In Vitro
investigations on the differential pro-oxidant and/or
antioxidant properties of cyclosporin A and tacrolimus in human
and rat liver microsomes.
Int J Clin Pharmacol Ther. 2006 May;44(5):225-32.
Institute of Pharmacology and Toxicology, Friedrich Schiller
University, 07740 Jena, Germany.
Amelie.Lupp@mti.uni-jena.de
OBJECTIVE: The use of cyclosporin A (CSA) and tacrolimus
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 tacrolimus and the involvement of the CYP system
were re-evaluated in vitro. METHODS: Effects of CSA and
tacrolimus 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 tacrolimus 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 tacrolimus 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.
PMID: 16724577
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