title: Investigation of CYP3A4 and CYP2D6 Interactions of Withania somnifera and Centella asiatica in Human Liver Microsomes.
abstract: Withania somnifera is commonly used as a rejuvenator, whereas Centella asiatica is well known for its anxiolytic and nootropic effects. The present study aims at investigating the effect of crude extracts and principal phytoconstituents of both the medicinal plants with CYP3A4 and CYP2D6 enzyme activity in human liver microsomes (HLM). Phytoconstituents were quantified in the crude extracts of both the medicinal plants using reverse phase HPLC. Crude extracts and phytoconstituents of W. somnifera showed no significant interaction with both CYP3A4 and CYP2D6 enzymes in HLM. Of the crude extracts of C. asiatica screened in vitro, methanolic extract showed potent noncompetitive inhibition of only CYP3A4 enzyme (Ki-64.36 ± 1.82 µg/mL), whereas ethanol solution extract showed potent noncompetitive inhibition of only CYP2D6 enzyme (Ki-36.3 ± 0.44 µg/mL). The flavonoids, quercetin, and kaempferol showed potent (IC50 values less than 100 μM) inhibition of CYP3A4 activity, whereas quercetin alone showed potent inhibition of CYP2D6 activity in HLM. Because methanolic extract of C. asiatica showed a relatively high percentage content of quercetin and kaempferol than ethanol solution extract, the inhibitory effect of methanolic extract on CYP3A4 enzyme activity could be attributed to the flavonoids. Thus, co-administration of the alcoholic extracts of C. asiatica with drugs that are substrates of CYP3A4 and CYP2D6 enzymes may lead to undesirable herb-drug interactions in humans.
authors: Department of Pharmacology, Shobhaben Pratapbhai Patel, School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai, India.
authors: Jay
authors: J
authors: Savai
authors: Alice
authors: A
authors: Varghese
authors: Nancy
authors: N
authors: Pandita
authors: Meena
authors: M
authors: Chintamaneni
mesh_terms: D028041:Centella / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D041743:Herb-Drug Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D044949:Kaempferols / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry; D011794:Quercetin / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology*; D032341:Withania / Q000737:chemistry
chemical_list: C526146:Centella asiatica extract; D065607:Cytochrome P-450 Enzyme Inhibitors; D044949:Kaempferols; D010936:Plant Extracts; D014315:Triterpenes; C006552:kaempferol; D011794:Quercetin; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A
keywords: C. asiatica; W. somnifera; cytochrome P450; herb-drug interactions; human liver microsomes