Abstract
Erythrina mulungu Benth. (Fabaceae), Cordia verbenacea A. DC. (Boraginaceae), Solanum paniculatum L. (Solanaceae) and Lippia sidoides Cham. (Verbenaceae) are medicinal plant species native to Brazil shortlisted by the Brazilian National Health System for future clinical use. However, nothing is known about their effects in metabolic and transporter proteins, which could potentially lead to herb-drug interactions (HDI). In this work, we assess non-toxic concentrations (100 μg/mL) of the plant infusions for their in vitro ability to modulate CYP3A4 mRNA gene expression and intracellular glutathione levels in HepG2 cells, as well as P-glycoprotein (P-gp) activity in vincristine-resistant Caco-2 cells (Caco-2 VCR). Their mechanisms of action were further studied by measuring the activation of human pregnane X receptor (hPXR) in transiently co-transfected HeLa cells and the inhibition of γ-glutamyl transferase (GGT) in HepG2 cells. Our results show that P-gp activity was not affected in any case and that only Solanum paniculatum was able to significantly change CYP3A4 mRNA gene expression (twofold decrease, p < 0.05), this being correlated with an antagonist effect upon hPXR (EC50 = 0.38 mg/mL). Total intracellular glutathione levels were significantly depleted by exposure to Solanum paniculatum (-44%, p < 0.001), Lippia sidoides (-12%, p < 0.05) and Cordia verbenacea (-47%, p < 0.001). The latter plant extract was able to decrease GGT activity (-48%, p < 0.01). In conclusion, this preclinical study shows that the administration of some of these herbal medicines may be able to cause disturbances to metabolic mechanisms in vitro. Although Erythrina mulungu appears safe in our tests, active pharmacovigilance is recommended for the other three species, especially in the case of Solanum paniculatum.
Highlights
According to the World Health Organization (WHO), 65–80% of the world’s population in developing countries depends on medicinal plants for their primary health care due to poverty or lack of access to modern medicine (Silveira et al, 2008)
It is an anti-inflammatory topical ointment marketed as Acheflan R, in which the active ingredient is the Brazilian medicinal plant Cordia verbenacea DC (Boraginaceae), a plant analyzed in this study (Calixto, 2005)
In a previous literature review, we revealed that such data are known for only half of the medicinal plants traditionally used in Brazil
Summary
According to the World Health Organization (WHO), 65–80% of the world’s population in developing countries depends on medicinal plants for their primary health care due to poverty or lack of access to modern medicine (Silveira et al, 2008). The MoH and the SUS surveyed municipalities nationwide and, using indications according to categories of the International Classification of Diseases, created the National List of Medicinal Plants of Interest to SUS (RENISUS)1 This list is composed of 71 plants, which have the potential to generate products of interest for the SUS, as well as promote the traditional practice of herbal remedies. As a result of this advancement, the first phytomedicine to be fully developed in Brazil was approved by ANVISA It is an anti-inflammatory topical ointment marketed as Acheflan R , in which the active ingredient is the Brazilian medicinal plant Cordia verbenacea DC (Boraginaceae), a plant analyzed in this study (Calixto, 2005)
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