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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 .

In vitro Effects of Four Native Brazilian Medicinal Plants in CYP3A4 mRNA Gene Expression, Glutathione Levels, and P-Glycoprotein Activity