AUTHOR=Mazzari Andre Luis Dias Araujo , Lacerda Mariella Guimarães , Milton Flora Aparecida , Mulin Montechiari Machado João Augusto , Sinoti Simone Batista Pires , Toullec Anne-Soulene , Rodrigues Patricia Marquez , Neves Francisco de Assis Rocha , Simeoni Luiz Alberto , Silveira Dâmaris , Prieto Jose Maria 

TITLE=In vitro effects of European and Latin-American medicinal plants in CYP3A4 gene expression, glutathione levels, and P-glycoprotein activity

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.826395

DOI=10.3389/fphar.2022.826395

ISSN=1663-9812

ABSTRACT=<p>Many medicinal plants species from European -such as <italic>Artemisia absinthium, Equisetum arvense, Lamium album, Malva sylvestris, Morus nigra, Passiflora incarnata, Frangula purshiana, and Salix alba</italic>- as well as Latin American traditions -such as <italic>Libidibia ferrea, Bidens pilosa, Casearia sylvestris, Costus spicatus, Monteverdia ilicifolia, Persea americana, Schinus terebinthifolia, Solidago chilensis</italic>, <italic>Syzygium cumini, Handroanthus impetiginosus,</italic> and <italic>Vernonanthura phosphorica-</italic> are shortlisted by the Brazilian National Health System for future clinical use. However, they lack many data on their action upon some key ADME targets. In this study, we assess non-toxic concentrations (up to100 μg/ml) of their infusions for <italic>in vitro</italic> 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). We further investigated the activation of human pregnane X receptor (hPXR) in transiently co-transfected HeLa cells and the inhibition of Gamma-glutamyl transferase (GGT) in HepG2 cells. Our results demonstrate <italic>L. ferrea, C. sylvestris</italic><italic>, M. ilicifolia, P. americana, S. terebinthifolia, S. cumini, V. phosphorica, E. arvense, P. incarnata, F. purshiana,</italic> and <italic>S. alba</italic> can significantly increase CYP3A4 mRNA gene expression in HepG2 cells. Only <italic>F. purshiana</italic> shown to do so likely via hPXR activation. P-gp activity was affected by <italic>L. ferrea, F. purshiana, S. terebinthifolia,</italic> and <italic>S. cumini</italic>. Total intracellular glutathione levels were significantly depleted by exposure to all extracts except <italic>S. alba</italic> and <italic>S. cumini</italic> This was accompanied by a lower GGT activity in the case of <italic>C. spicatus, P. americana, S. alba,</italic> and <italic>S. terebinthifolia</italic>, whilst <italic>L. ferrea</italic>, <italic>P. incarnata</italic> and <italic>F. purshiana</italic> increased it. Surprisingly, <italic>S. cumini</italic> aqueous extract drastically decreased GGT activity (−48%, <italic>p</italic> &lt; 0.01). In conclusion, this preclinical study shows that the administration of some of these herbal medicines causes <italic>in vitro</italic> disturbances to key drug metabolism mechanisms. We recommend active pharmacovigilance for <italic>Libidibia ferrea</italic> (Mart.) L. P. Queiroz, <italic>Frangula purshiana</italic> Cooper, <italic>Schinus terebinthifolia</italic> Raddi, and <italic>Salix alba</italic> L. which were able to alter all targets in our preclinical study.</p>