Hyperforin and its analogues inhibit CYP3A4 enzyme activity

• Published in: Phytochemistry (Oxford) Vol. 67; no. 23; pp. 2550 - 2560
• Main Authors: Lee, Ju-young, Duke, Rujee K., Tran, Van H., Hook, James M., Duke, Colin C.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.12.2006; Elsevier
• Subjects: acylhloroglucinols; Acylphloroglucinols; Biochemistry & Molecular Biology; Biological and medical sciences; Bridged Bicyclo Compounds - chemistry; Bridged Bicyclo Compounds - isolation & purification; Bridged Bicyclo Compounds - pharmacology; Chemical constitution; cytochrome P-450; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; enzyme activity; enzyme inhibition; Fundamental and applied biological sciences. Psychology; Furoadhyperforin; Furohyperforin; General pharmacology; Humans; Hyperforin; Hypericum - chemistry; Hypericum perforatum; isozymes; Life Sciences & Biomedicine; Medical sciences; medicinal plants; Molecular Structure; MS and CYP3A4 enzyme; NMR; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Phloroglucinol - analogs & derivatives; Phloroglucinol - chemistry; Phloroglucinol - isolation & purification; Phloroglucinol - pharmacology; Plant physiology and development; Plant Sciences; recombinant proteins; Science & Technology; St. John’s wort; Terpenes - chemistry; Terpenes - isolation & purification; Terpenes - pharmacology; Hyperforin; St. John’s wort; NMR; Acylphloroglucinols; Furohyperforin; Furoadhyperforin; MS and CYP3A4 enzyme; ADHYPERFORIN; DEPRESSION; HYPERICUM-PERFORATUM; hyperforin; furohyperforin; INDUCTION; CYTOCHROME-P450 3A4; MASS-SPECTROMETRY; furoadhyperforin; METABOLISM; ST-JOHNS-WORT; St. John's wort; acylphloroglucinols; EXTRACT; CONSTITUENTS; Cytochrome P450; Gene expression; Metabolism; Biological activity; Enzymatic activity; Plant origin; Inhibition
• ISSN: 0031-9422; 1873-3700
• DOI: 10.1016/j.phytochem.2006.09.018

Hyperforin and its four oxidized analogues were isolated from St. John’s wort and evaluated for their effects on CYP3A4 enzyme activity. Literature indicates that herb–drug interaction of St. John’s wort is largely due to increased metabolism of the co-administered drugs that are the substrates of cytochrome P450 (CYP) 3A4 enzyme, alteration of the activity and/or expression of the enzyme. The major St. John’s wort constituents, acylphloroglucinols, were evaluated for their effects on CYP3A4 enzyme activity to investigate their roles in herb–drug interaction. Hyperforin and four oxidized analogues were isolated from the plant and fully characterized by mass spectral and NMR analysis. These acylphloroglucinols inhibited activity of CYP3A4 enzyme potently in the fluorometric assay using the recombinant enzyme. Furoadhyperforin (IC 50 0.072 μM) was found to be the most potent inhibitor of CYP3A4 enzyme activity, followed by furohyperforin isomer 1 (IC 50 0.079 μM), furohyperforin isomer 2 (IC 50 0.23 μM), hyperforin (IC 50 0.63 μM) and furohyperforin (IC 50 1.3 μM). As the acylphloroglucinols are potent inhibitors of the CYP3A4 enzyme, their modulation of the enzyme activity is unlikely to be involved in increased drug metabolism by St. John’s wort.