REGULATION OF THE ACTIVITY OF DRUG METABOLISM ENZYMES –CYTOCHROMES P450 3A4 AND 2C9 BY BIOLOGICALLY ACTIVE COMPOUNDS

A.A. Makhova (1), V.V. Shumyantseva (2), E.V. Shikh (1), T.V. Bulko (2), E.V. Suprun (2), A.V. Kuzikov (2), V.G. Kukes (1), A.I. Archakov (2)
1 -Sechenov First Moscow State Medical University
2 -Orekhovich Institute of Biomedical Chemistry, Moscow

A study of the influence of vitamins with antioxidant properties (vitamins A, E, C, coenzyme Q10), drugs, antioxidants (etoksidol, meksidol, cytochrome c), B vitamins (В1, В2, В6), and vitamin-like substances taurine and L-carnitine on the phase I xenobiotic-metabolizing enzymes – cytochrome P450 3A4 and 2C9 was performed. In experiments with participation of informed volunteers it was shown that B vitamins allow to reduce the duration of therapy with non-steroidal anti-inflammatory drug diclofenac (Voltaren), and diminish the daily requirement of diclofenac. There was shown also a positive effect of B vitamins on the release of pain, allowing to shorten the duration of treatment and decline the daily requirement of diclofenac.. Pharmacodynamic and pharmacokinetic data were confirmed in experiments on the study of electrocatalytic activity of cytochrome P450 3A4 (CYP3A4) by electrochemical methods. An electrochemical approach to the study of the catalytic activity of cytochrome P450 and the influence of biologically active compounds on electrocatalysis is sensitive and effective sensor method that allows to use low concentrations of the protein on the electrode (to 10–15 mol/ electrode), to perform an analysis without protein partners (cytochrome B5 NADPH-dependent reductase), and to identify the interaction of drugs in pre-clinical experiments. In the comparison of the influence of B vitamins (В1, В2, В6) in the same concentration (300 mcM) according to an electrochemical analysis, riboflavin (vitamin B2) is most effectively inhibits the interaction of diclofenac with cytochrome P450 3A4. Vitamin-like substance taurine, possessing antioxidant properties, antioxidant vitamins and medicines with antioxidant properties stimulated electrochemical reduction of cytochromes P450 3A4 and P450 2C9. The obtained data support the availability of regulation of the pharmacokinetic parameters and the pronouncement of the pharmacodynamic effect with the help of the impact of vitamins on the activity of cytochrome P450 3A4 (CYP3A4) and P450 2C9 (CYP2C9).
Keywords: 
cytochrome P450 3A4, diclofenac, antioxidants, electrochemistry, enzyme electrodes, vitamins A, C, E, B group vitamins, interaction