The Effect of New
Lipophilic Chelators on the Activities of Cytosolic Reductases
and P450 Cytochromes Involved in the Metabolism of Anthracycline
Antibiotics: Studies in Vitro
L. SCHRÖTEROVÁ, H. KAISEROVÁ, V. BALIHAROVÁ, J. VELÍK,
V. GERŠL1, E. KVASNIČKOVÁ
Department of Biochemical Sciences, Faculty of Pharmacy, Charles
University and
1Department of Pharmacology, Faculty of Medicine,
Charles University, Hradec Králové,
Czech Republic
Received August 4, 2003
Accepted January 22, 2004
Summary
A major obstacle to the therapeutic use of anthracyclines,
highly effective anticancer agents, is the fact that their
administration results in dose-dependent cardiomyopathy.
According to the currently accepted hypothesis, anthracyclines
injure the heart by generating oxygen free radicals. The ability
of pyridoxal isonicotinoyl hydrazone (PIH) and salicylaldehyde
isonicotinoyl hydrazone (SIH) – new iron chelators – to protect
against peroxidation as well as their suitable biological,
physical and chemical properties make the compounds promising
candidates for pre-clinical and clinical studies. Activities of
carbonyl reductase CR (1.1.1.184), dihydrodiol dehydrogenase DD2
(1.3.1.20), aldehyde reductase ALR1 (1.1.1.2) and P450
isoenzymes (CYP1A1, CYP1A2, CYP2B, CYP3A) involved in the
metabolism of daunorubicin, doxorubicin and other drugs or
xenobiotics were studied. Various concentrations of the
chelators were used either alone or together with daunorubicin
or doxorubicin for in vitro studies in isolated hepatocytes. A
significant decrease of activity was observed for all enzymes
only at PIH and SIH concentrations higher than those presumed to
be used for therapy. The results show that PIH and SIH have no
effect on the activities of the enzymes studied in vitro and
allow us to believe that they will not interfere with the
metabolism of co-administered drugs and other xenobiotics.
Daunorubicin (Da) and doxorubicin (Dx) significantly reduce
cytochrome P450 activity, but the addition of SIH and PIH
chelators (50 μM) reverses the reduction and restores the
activity to 70-90 % of the activity of relevant controls.
Key words
Oxidative stress • P450 • Cytosolic reductases • Iron chelators
• Pyridoxal isonicotinoyl hydrazone
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