ToxSci Advance Access published online on July 11, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg174
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157 Milan, Italy
* To whom correspondence should be addressed. E-mail: cantoni{at}marionegri.it.
This study in mice investigated whether hyperforin accounts for the inductive effects on cytochrome P4503A enzymes of St. John's wort extracts (SJW) (Hypericum perforatum), one of the most popular herbal preparations because of its alleged activity in mild to moderate depression. An hydroalcoholic extract containing 4.5% hyperforin was given at a dose of 300 mg/kg b.i.d. for 4 and 12 days. Hyperforin, its main phloroglucinol component, was given as dicyclohexylammonium (DCHA) salt (18.1 mg/kg, b.i.d.) on the basis of its content in the extract, to ensure comparable exposure to hyperforin. The extract increased hepatic erythromycin-N-demethylase (ERND) activity, which is cytochrome P450 enzyme (CYP) 3A-dependent, about 2.2-fold after four days of dosing, with only slightly greater effect after 12 days (2.8 times controls). Hyperforin too increased ERND activity within four days much the same extent as the extract (1.8 times the activity of controls), suggesting that it behaves qualitatively and quantitatively like the extract as regards induction of CYP3A activity. This effect was confirmed by Western blot analysis of hepatic CYP3A expression. Exposure to hyperforin at the end of the four days' treatment was still similar to that with SJW extract, although it was variable and lower than after the first dose in both cases, further suggesting that hyperforin plays a key role in CYP3A induction by the SJW extract in the mouse. Standardization of the extracts based on the hyperforin content can be proposed for further evaluation of their potential action on first-pass metabolism and clearance of co-administered CYP3A substrates.
© 2003 Society of Toxicology
Biotransformation and Toxicokinetics
Hyperforin Contributes to the Hepatic CYP3A-Inducing Effect of Hypericum perforatum Extract in the Mouse
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