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Hyperforin and its analogues inhibit CYP3A4 enzyme activity
Ju-young Lee1, Rujee K Duke, Van H Tran
1Pharmaceutical Chemistry, Faculty of Pharmacy, University of Sydney, Building A15, Science Road, Sydney, NSW 2006, Australia.
Phytochemistry
|November 7, 2006
Summary
St. John's wort constituents, acylphloroglucinols, were studied for their impact on cytochrome P450 3A4 (CYP3A4) enzyme activity. These compounds potently inhibited CYP3A4, suggesting they are not responsible for increased drug metabolism observed with St. John's wort.
Area of Science:
- Pharmacology
- Natural Product Chemistry
- Drug Metabolism
Background:
- St. John's wort is known to cause herb-drug interactions, primarily by affecting cytochrome P450 3A4 (CYP3A4) enzyme activity.
- Acylphloroglucinols are major constituents of St. John's wort and are suspected to play a role in these interactions.
Purpose of the Study:
- To investigate the effects of major St. John's wort constituents, acylphloroglucinols, on CYP3A4 enzyme activity.
- To determine the role of these compounds in the herb-drug interactions associated with St. John's wort.
Main Methods:
- Isolation and characterization of acylphloroglucinols (hyperforin and four oxidized analogues) from St. John's wort using mass spectral and NMR analysis.
- Evaluation of the inhibitory effects of isolated acylphloroglucinols on CYP3A4 enzyme activity using a fluorometric assay with recombinant CYP3A4.
Main Results:
- All tested acylphloroglucinols demonstrated potent inhibition of CYP3A4 enzyme activity.
- Furoadhyperforin (IC50 0.072 μM) was the most potent inhibitor, followed by furohyperforin isomer 1 (IC50 0.079 μM), furohyperforin isomer 2 (IC50 0.23 μM), hyperforin (IC50 0.63 μM), and furohyperforin (IC50 1.3 μM).
Conclusions:
- Acylphloroglucinols are potent inhibitors of CYP3A4 enzyme activity.
- The observed potent inhibition of CYP3A4 by acylphloroglucinols suggests their modulation of enzyme activity is unlikely to be the mechanism behind the increased drug metabolism associated with St. John's wort.
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