Cyclosporin-A-induced lipid peroxidation in human liver microsomes and its influence on cytochrome P-450.
The present in vitro study using human liver tissue was performed to investigate the effect of cyclosporin A on lipid peroxidation and cytochrome P-450 concentration in isolated liver microsomes. Incubations were either carried out with cyclosporin A concentrations of 10, 30, 100 and 300 micrograms ml-1 for 1 h or for different time periods (15, 30, 60 and 90 min) with cyclosporin A 300 micrograms ml-1. Lipid peroxidation was monitored measuring the amount of malondialdehyde. In additional experiments the effect of reduced and oxidized glutathione (1 mM) on cyclosporin-A-induced lipid peroxidation in human liver microsomes was studied. Cyclosporin A caused a significant dose and time-dependent increase of the lipid peroxidation product malondialdehyde. At the highest cyclosporin A concentration (300 micrograms ml-1) malondialdehyde production increased 5-fold in comparison to corresponding control values. Incubations for different time periods resulted in a 5-fold net increase of malondialdehyde formation after 90 min. In the presence of reduced glutathione, cyclosporin-A-induced lipid peroxidation was significantly inhibited. Furthermore, cyclosporin-A-induced microsomal lipid peroxidation was accompanied by a significant dose-dependent decline of the microsomal cytochrome P-450 content. At a cyclosporin A concentration of 300 micrograms ml-1, cytochrome P-450 content was decreased to 49% in comparison to control values. In the presence of reduced glutathione, cyclosporin A decreased the cytochrome P-450 concentration only to 79% (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Inselmann
G
G
1 Medizinische Klinik, Christian-Albrechts-Universität Kiel, Germany.
Barth
A
A
Engemann
R
R
Heidemann
H T
HT
D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism
D008315:Malondialdehyde; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System