A Mechanism of O-Demethylation of Aristolochic Acid I by Cytochromes P450 and Their Contributions to This Reaction in Human and Rat Livers: Experimental and Theoretical Approaches
Abstract
:1. Introduction
2. Results and Discussion
2.1. Effect of CYP Enzyme Inhibitors on AAI O-Demethylation Catalyzed by Human and Rat Hepatic Microsomes
Inhibitor a | AAIa Formation (% of Control without Inhibitor) | |
---|---|---|
Human Microsomes | Rat Microsomes | |
α-Napththoflavone (CYP1A1/2) | 89 ± 5 * | 85 ± 5 ** |
Furafylline (CYP1A2) | 75 ± 4 ** | 84 ± 5 ** |
Diamantane (CYP2B) | NI b | NI |
Sulfaphenazole (CYP2C) | NI | 68 ± 3 *** |
Quinidine (CYP2D) | NI | NI |
DDTC (CYP2A, CYP2E1) | 96 ± 5 | 52 ± 4 *** |
Ketoconazole (CYP3A) | 74 ± 4 ** | 90 ± 4 * |
2.2. O-Demethylation of AAI to AAIa by Human and Rat Recombinant CYPs in Supersomes™
2.3. Contributions of Individual CYPs to AAIa Formation in Human and Rat Livers
2.4. Binding of AAI to the Active Sites of Compounds I of Human CYP1A1, 1A2, 2C9, and 3A4
Simulated System | The Most Stable Productive Orientations of AAI in the Complex with CYP | |
---|---|---|
Estimated Free Energy of Binding (kcal/mol) | O(Comp I)-OCH3 (AAI) Distance [Å] a | |
CYP1A1 | −7.0 | 4.4 |
CYP1A2 | −7.7 | 4.9 |
CYP2C9 | −5.3 | 4.3 |
CYP3A4 | −6.0 | 3.7 |
3. Experimental Section
3.1. Supersomes™
3.2. Preparation of Rat Hepatic Microsomes
3.3. Microsomal Incubations to Study AAI O-Demethylation
3.4. Inhibition Studies
3.5. Contributions of CYP Enzymes to O-Demethylation of AAI in Human and Rat Livers
3.6. Molecular Docking of AAI into Compounds I of Human CYP1A1, 1A2, 2C9, and 3A4
3.7. Statistical Analyses
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Stiborová, M.; Bárta, F.; Levová, K.; Hodek, P.; Schmeiser, H.H.; Arlt, V.M.; Martínek, V. A Mechanism of O-Demethylation of Aristolochic Acid I by Cytochromes P450 and Their Contributions to This Reaction in Human and Rat Livers: Experimental and Theoretical Approaches. Int. J. Mol. Sci. 2015, 16, 27561-27575. https://doi.org/10.3390/ijms161126047
Stiborová M, Bárta F, Levová K, Hodek P, Schmeiser HH, Arlt VM, Martínek V. A Mechanism of O-Demethylation of Aristolochic Acid I by Cytochromes P450 and Their Contributions to This Reaction in Human and Rat Livers: Experimental and Theoretical Approaches. International Journal of Molecular Sciences. 2015; 16(11):27561-27575. https://doi.org/10.3390/ijms161126047
Chicago/Turabian StyleStiborová, Marie, František Bárta, Kateřina Levová, Petr Hodek, Heinz H. Schmeiser, Volker M. Arlt, and Václav Martínek. 2015. "A Mechanism of O-Demethylation of Aristolochic Acid I by Cytochromes P450 and Their Contributions to This Reaction in Human and Rat Livers: Experimental and Theoretical Approaches" International Journal of Molecular Sciences 16, no. 11: 27561-27575. https://doi.org/10.3390/ijms161126047