[Role of antioxidants in electro catalytic activity of cytochrome P450 3A4].

Abstract

The electrochemical analysis of cytochrome R450 3A4 catalytic activity has shown that vitamins C, A and Ye influence on electron transfer and Fe3+/Fe2+ reduction process of cytochrome R450 3A4. These data allow to assume possibility of cross effects and interference of vitamins-antioxidants with drugs metabolised by cytochrome R450 3A4, at carrying out of complex therapy. This class of vitamins shows antioxidant properties that lead to increase of the cathodic current corresponding to heme reduction of this functionally significant haemoprotein. Ascorbic acid of 0.028-0.56 mM concentration stimulates cathodic peak (an electrochemical signal) of cytochrome R450 3A4. At the presence of diclofenac (Voltaren) - a typical substrate of cytochrome R450 3A4 - the increase growth of a catalytic current testifying to an electrocatalysis and stimulating action of ascorbic acid is observed. In the presence of vitamins A and Ye also is registered dose-dependent (in a range of 10-100 M) increase in a catalytic current of cytochrome R450 3A4: the maximum increase corresponds to 229 ± 20% for 100 M of vitamin A, and 162±10% for 100 M of vitamin E. Vitamin E in the presence of P450's inhibitor itraconazole doesn't give essential increase in a reductive current, unlike retinol (vitamin A). This effect can manifest substrate properties of tocopherol (vitamin E). The electrochemical approach for the analysis of catalytic activity of cytochrome R450 3A4 and studies of influence of biologically active compounds on an electrocatalysis is the sensitive and effective sensor approach, allowing to use low concentration of protein on an electrode (till 10-15 mol/electrode), to carry out the analysis without participation of protein redox partners, and to reveal drug-drug or drug-vitamins interaction in pre-clinical experiments.