Abstract
It has been well reported that complementary medicines can significantly alter the way the body handles conventional drugs, leading to potential fatal herb-drug interactions. The aim of the present study was to investigate the molecular mechanism of drug interactions involving St John's wort (SJW) (Hypericum perforatum L), a popular herbal medicine widely used for depression, particularly examining changes in the expression of cytochrome P450 CYP3A, the most abundant drug metabolising CYP enzymes in man.Eighteen Sprague-Dawley (SD) rats were assigned randomly into 3 groups (n = 6/group): control, low dose and high dose (500 and 1000 mg/kg/day of SJW, equal to 1500 and 3000 µg/kg/day of Hypericin). Each group was treated with SJW or control preparation, by gastric gavage, for 14 consecutive days. Liver and intestinal CYP3A activity and protein and mRNA levels, from five segments of the intestine, were examined using CYP3A-dependent erythromycin N-demethylation activity assay, quantitative immuno-blotting and real-time RT-PCR.Increase in CYP3A activity and protein level by SJW was observed in some intestinal regions, with a 3.0 fold increase in liver CYP3A activity and a 10.6 fold increase in liver CYP3A1 mRNA (p < 0.05) in a dose dependent manner. The results suggested that up regulation of liver CYP3A mRNA and differential induction of intestinal CYP3A play an important role in the molecular mechanism of herb-drug interactions.
Highlights
Complementary medicines are widely available in the community and their uses have grown dramatically in the Western world
While hypericin is the component of St John’s wort (SJW) primarily believed to be responsible for its antidepressant activity, hyperforin is the most likely to cause of CYP3A inhibition and induction (Obach, 2000)
CYP3Adependent erythromycin N-demethylation activity was higher in some segments of the intestine prepared from the SJW high dose treated group in comparison to the control group
Summary
Complementary medicines are widely available in the community and their uses have grown dramatically in the Western world. Since many different preparations of SJW are available over-the-counter and may be taken without medical consultation, there are significant concerns regarding interactions linked to the use of SJW products in combination with conventional medicines (Henderson et al 2002; Martin-Facklam et al 2004; Mai et al 2004). The constituent hypericin has been reported to be the most likely candidate to be responsible for the antidepressant activity and is commonly used to standardise the various SJW products (Henderson et al 2002). While hypericin is the component of SJW primarily believed to be responsible for its antidepressant activity, hyperforin is the most likely to cause of CYP3A inhibition and induction (Obach, 2000)
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