title: Inhibitory effects of Phyllanthus amarus and its major lignans on human microsomal cytochrome P450 activities: evidence for CYP3A4 mechanism-based inhibition.
abstract: Phyllanthus amarus has long been used as a herbal medicine in several countries. Phytochemicals in herbal medicine may interact with cytochromes P450 (CYP) and thus raise the potential of herb-drug interactions; therefore, the inhibitory effects of P. amarus and its major phytochemicals phyllanthin and hypophyllanthin on CYP isoforms were determined using human liver microsomes and selective substrates. Both ethanolic and aqueous extracts of P. amarus inhibited CYP1A2, CYP2D6, CYP2E1 and CYP3A4 in a dose-dependent manner. Compared to known CYP3A inhibitors, the IC(50) values of the ethanolic and aqueous extracts on testosterone 6β-hydroxylation were higher than that of ketoconazole but were lower than those of erythromycin and clarithromycin. Both extracts were weak inhibitors of CYP1A2, CYP2D6 and CYP2E1. In addition, phyllanthin and hypophyllanthin were potent mechanism-based inhibitors of CYP3A4 with K(I) values of 1.75 ± 1.20 µM and 2.24 ± 1.84 µM and k(inact) values of 0.18 ± 0.05 min(-1) and 0.15 ± 0.06 min(-1), respectively. The k(inact)/K(I) ratios of these lignans were higher than those reported for some therapeutic drugs that act as mechanism-based inhibitors of CYP3A4. These results suggest that co-administration of P. amarus with drugs that are metabolized by CYP3A4 may potentially result in herb-drug interactions.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand.
authors.forename: Theerada
authors.initials: T
authors.lastname: Taesotikul
authors.forename: Weeraya
authors.initials: W
authors.lastname: Dumrongsakulchai
authors.forename: Nitsupa
authors.initials: N
authors.lastname: Wattanachai
authors.forename: Vichien
authors.initials: V
authors.lastname: Navinpipat
authors.forename: Aimon
authors.initials: A
authors.lastname: Somanabandhu
authors.forename: Wongwiwat
authors.initials: W
authors.lastname: Tassaneeyakul
authors.forename: Wichittra
authors.initials: W
authors.lastname: Tassaneeyakul
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D041743:Herb-Drug Interactions / Q000502:physiology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000494:pharmacology; D017705:Lignans / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D029803:Phyllanthus / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D017705:Lignans; D010936:Plant Extracts; C512682:hypophyllanthin; C517985:phyllanthin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole