Hypericin and hyperforin

As an herbal remedy, Hypericum perforatum has not been subjected to the rigorous clinical testing of modern drug candidates. Several recent reports provide evidence that St. John's wort promotes the metabolism of coadministered drugs, including the HIV protease inhibitor indinavir, the immunosuppressant cyclosporin, and oral contraceptives. Because each of these drugs is metabolized by cytochrome P450 (CYP) 3 A4, a monooxygenase involved in the metabolism of many xenobiotics, these findings suggested that St. John's wort might induce CYP3A4 expression. Transcription of CYP3A4 is known to be induced by a range of xenobiotics, including drugs such as the antibiotic rifampicin, the antimycotic clotrimazole, the insulinsensitizer troglitazone, and the barbiturate phenobarbital.

Hyperforin and H. perforatum extracts induce CYP3A4 in hepatocyte cells via the pregnane X nuclear receptor which controls CYP3A4 expression. The crude extracts of H. perforatum inhibit CYP2C9, CYP2CI9, CYP2D6 and CYP3A4. The extracts were further fractioned and each fraction was tested for inhibitory action on the cytochrome P450 (CYP) enzyme activities.

Hyperforin, amentoflavone, hypericin, quercetrin and chlorogenic acid, all demonstrated inhibitory affect on cytochrome P450 (CYP) enzyme activities. Amentoflavone was shown to be potent inhibitor of CYP3A4, CYP1A2 and CYP2C9. Hyperforin was shown as potent non-competitive inhibitor of CYP2C9, CYP2D6 and CYP3A4. Hypericin also demonstrated inhibitory activity. The author concluded that H. perforatum extracts contains compounds that have potent inhibitory activity on major drug metabolizing enzymes.

A study investigated the effect of H. perforatum on cytochrome CYP2D6 and CYP3A4. Seven healthy volunteers were orally administered alprazolam and dextromethorphan along with H. perforatum. Urinary concentrations of alprazolam and dextromethorphan and dextromethorphan metabolic ratios were determined. The authors concluded no significant difference in pharmacokinetic profile of alprazolam or dextromethorphan metabolic ratios.

In a human study, 13 healthy volunteers were given 300mg standardized extract H. perforatum TID for 14 d. 24 h urinary excretion ratios of 6-betahydroxycortisol/ cortisol were used as an index of CYP3A4 activity. A significant increase, from zero up to around 2.5x over base was found in urinary ratios in 12 subjects, suggestive of 3A4 induction.

According to a study, researchers were able to determine the structure of a significant molecule (PXR) present in the liver and responsible for the metabolism of a majority of the drugs consumed by humans. The molecule is a regulator of the protein known as P450-3A, which is responsible for breaking the drugs. Recently interactions of H. perforatum have been suggested with oral contraceptives, antivirals and transplant drugs.

A study reported that hyperforin contributes to the hepatic CYP3A-inducing effect of H. perforatum extract in the mouse. A hydro alcoholic extract containing 4.5% hyperforin was given at a dose of 300 mg/kg b.i.d. for 4 and 12 d. Hyperforin, its main phloroglucinol component, was given as dicyclohexylammonium 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 activity, which is cytochrome P450 enzyme (CYP) 3A-dependent, about 2.2-fold after 4 d of dosing, with only slightly greater effect after 12 d (2.8 times controls).

Hyperforin too increased erythromycin-N-demethylase activity within 4 d to 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 extract of H. perforatum, 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 extract of H. perforatum in the mouse.

In a subsequent study, it was shown that hyperforin induces the expression of numerous drug metabolism and excretion genes in primary human hepatocytes. The researchers determined the crystal structure of hyperforin in complex with the ligand binding domain of human PXR. Hyperforin induces conformational changes in PXR's ligand binding pocket relative to structures of human PXR elucidated previously and increases the size of the pocket by 250 A. It was found that the mutation of individual aromatic residues within the ligand binding cavity changes PXR's response to particular ligands. Taken together, these results demonstrate that PXR employs structural flexibility to expand the chemical space it samples and that the mutation of specific residues within the ligand binding pocket of PXR tunes the receptor's response to ligands.

Recently it has been reported that H. perforatum can reduce the efficacy of chemotherapy drug known as irinotecan. The study was based on previous findings that H. perforatum can stimulate cytochrome P450 (CYP3A4), an enzyme system involved in drug metabolism. Specifically, researchers took the premise that hypericin and hyperforin-components of H. perforatum seem to enhance CYP3A4 activity and the fact that irinotecan is also partly metabolized by the enzyme system (see Fig. 6.20).



Hyperforin Perforatum

CYP3A4 protein

""" Oxidised irinotecan (inactive)

CYP3A4 protein

""" Oxidised irinotecan (inactive)



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