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CYP2C19 progress curve analysis and mechanism-based inactivation by three methylenedioxyphenyl compounds
Kaisa A Salminen1, Achim Meyer, Peter Imming
1School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. kaisa.salminen@uef.fi
Drug Metabolism and Disposition: the Biological Fate of Chemicals
|September 13, 2011
Summary
Three herbal alkaloids, bulbocapnine, canadine, and protopine, are new mechanism-based inactivators of CYP2C19. These methylenedioxyphenyl (MDP) compounds show quasi-irreversible inactivation, identified using CYP2C19 progress curve analysis.
Area of Science:
- Biochemistry
- Pharmacology
- Drug Metabolism
Background:
- Cytochrome P450 enzymes, particularly CYP2C19, play crucial roles in drug metabolism.
- Isoquinoline alkaloids found in herbal medicines can potentially interact with drug-metabolizing enzymes.
- Understanding these interactions is vital for predicting drug efficacy and toxicity.
Purpose of the Study:
- To investigate whether bulbocapnine, canadine, and protopine are mechanism-based inactivators of CYP2C19.
- To characterize the kinetics of inactivation and confirm criteria for mechanism-based inhibition.
- To evaluate the utility of CYP2C19 progress curve analysis for identifying novel inactivators.
Main Methods:
- Utilized fluorometric CYP2C19 progress curve analysis to assess time-dependent inhibition.
- Determined inactivation kinetics (K(I) and k(inact)) for each alkaloid.
- Performed additional experiments to confirm NADPH dependence, irreversibility, and metabolic intermediate complex formation.
Main Results:
- Bulbocapnine, canadine, and protopine demonstrated time-dependent and saturable inactivation of CYP2C19.
- Specific K(I) and k(inact) values were determined for each compound.
- Evidence of quasi-irreversible inactivation was confirmed through NADPH-dependence and spectral analysis.
Conclusions:
- The CYP2C19 progress curve analysis is an effective method for identifying mechanism-based inactivators.
- Bulbocapnine, canadine, and protopine are novel mechanism-based inactivators of CYP2C19.
- These alkaloids represent the first methylenedioxyphenyl (MDP) compounds exhibiting quasi-irreversible inactivation of CYP2C19, with implications for herbal medicine-drug interactions.
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