Biomedical Chemistry: Research and Methods 2022, 5(2), e00176

Electrochemical Analysis of Metabolites as a Method for Cytochromes P450 Activity Determination

A.V. Kuzikov1,2, R.A. Masamrekh1,2, T.A. Filippova1,2, V.V. Shumyantseva1,2*

1Pirogov Russian National Research Medical University, 1 Ostrovityanova str. Moscow 117997, Russia;
*e-mail: v_shumyantseva@mail.ru

2Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow, 119121 Russia

Keywords:cytochromes P450; drugs; metabolites; electrochemistry

DOI:10.18097/BMCRM00176

The whole version of this paper is available in Russian.

The review deals with the electrochemical methods for determination of metabolites of cytochromes P450 catalyzed reactions. We have focused on the electrochemical determination of metabolites of drugs and some endogenous compounds. We have reviewed bielectrode systems for determination of cytochrome P450 activity, where one electrode serves as a matrix for enzyme immobilization and a source of electrons for heme iron ion reduction and initialization of the catalytic reaction towards a substrate and the second one is being used for quantification of the products formed by their electrochemical oxidation. Such systems allow one to elude additional steps of separation of reaction substrates and products. The review also includes discussion of the ways to increase the analytical sensitivity and decrease the limit of detection of the investigated metabolites by chemical modification of electrodes. We demonstrate the possibilities of these systems for cytochrome P450 kinetics analysis and the perspectives of their further improvement, such as increasing the sensitivity of metabolite electrochemical determination by modern electrode modificators, including carbon-based, and construction of devices for automatic monitoring of the products.
Figure 1. The general mechanism of the electrochemical oxidation of hydroxyphenyl-containing compounds. Adapted from [58].
Figure 2. The reaction of (S)-warfarin metabolism catalyzed by CYP2C9.
Figure 3. Square-wave voltammograms of 0.1 M potassium-phosphate buffer (pH 7.4) containing 0.05 М NaCl, 1% methanol (v/v) (‒), 100 µM (S)-warfarin (‒ ‒ ‒) or 100 µM (S)-7-hydroxywarfarin (· · ·). Square wave frequency, 25 Hz.
Figure 4. The reaction of mianserin metabolism catalyzed by CYP1A2 and CYP2D6.
Figure 5. The reactions of imipramine metabolism catalyzed by CYP2C19, CYP1A2, CYP3A4 and CYP2D6. Adapted from [23].
Figure 6. The reactions of diclofenac metabolism catalyzed by CYP2C9 and CYP3A4.
Figure 7. The reactions of piroxicam and lornoxicam metabolism catalyzed by CYP2C9.
Figure 8. The reaction of chlorpromazine metabolism catalyzed by CYP2D6.
Figure 9. The reactions of propranolol metabolism catalyzed by CYP2D6.
Figure 10. The reaction of (S)-naproxen metabolism catalyzed by CYP1A2 and CYP2C9.
Figure 11. Square-wave voltammograms of 0.1 M potassium-phosphate buffer (pH 7.4) containing 0.05 М NaCl, 1% methanol (v/v) (‒), 100 µM (S)-naproxen (‒ ‒ ‒) or 100 µM (S)-O-desmethylnaproxen (· · ·). Square wave frequency, 25 Hz.
Figure 12. The reaction of phenacetin metabolism catalyzed by CYP1A2.
Figure 13. The reaction of codeine metabolism catalyzed by CYP2D6.
Figure 14. The reaction of codeine metabolism catalyzed by CYP2D6.
Figure 15. The principle of functioning of bielectrode systems based on immobilized cytochromes P450 (enzyme electrode) and electrochemical determination of the enzymatic reaction product (measuring electrode).

CLOSE
Table 1. Catalyzed by CYPs reactions of drug metabolism resulting in hydroxyl group formation in aromatic rings.

FUNDING

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Supplementary materials are available at http://dx.doi.org/10.18097/BMCRM00174

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