title: In vitro effects of active constituents and extracts of Orthosiphon stamineus on the activities of three major human cDNA-expressed cytochrome P450 enzymes.
abstract: Orthosiphon stamineus (OS) has been traditionally used to treat diabetes, kidney and urinary disorders, high blood pressure and bone or muscular pain. To assess the possibility of drug-herb interaction via interference of metabolism, effects of four OS extracts of different polarity and three active constituents (sinensetin, eupatorin and rosmarinic acid) on major human cDNA-expressed cytochrome P450 (CYP) enzymes were investigated. Three substrate-probe based high-performance liquid chromatography (HPLC) assays were established to serve as activity markers for CYP2C9, CYP2D6 and CYP3A4. Our results indicate that OS extracts and constituents exhibited differential modulatory effects on different CYPs. While none of the OS components showed significant inhibition on CYP2C9, eupatorin strongly and uncompetitively inhibited CYP2D6 activity with a K(i) value of 10.2μM. CYP3A4 appeared to be the most susceptible enzyme to OS inhibitory effects. It was moderately inhibited by OS dichloromethane and petroleum ether extract with mixed-type and noncompetitive inhibitions (K(i)=93.7 and 44.9μg/mL), respectively. Correlation study indicated that the inhibition was accounted for by the presence of eupatorin in the extracts. When IC(50) values of these extracts were expressed in volume per dose unit to reflect inhibitory effect at recommended human doses from commercially available products, moderate inhibition was also observed. In addition, CYP3A4 was strongly and noncompetitively inhibited by eupatorin alone, with a K(i) value of 9.3μM. These findings suggest that co-administration of OS products, especially those with high eupatorin content, with conventional drugs may have the potential to cause drug-herb interactions involving inhibition of major CYP enzymes.
authors.affiliation: School of Pharmacy and Health Sciences, International Medical University, 126, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Yan
authors.initials: Y
authors.lastname: Pan
authors.forename: Badrul Amini
authors.initials: BA
authors.lastname: Abd-Rashid
authors.forename: Zakiah
authors.initials: Z
authors.lastname: Ismail
authors.forename: Rusli
authors.initials: R
authors.lastname: Ismail
authors.forename: Joon Wah
authors.initials: JW
authors.lastname: Mak
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Pook
authors.forename: Hui Meng
authors.initials: HM
authors.lastname: Er
authors.forename: Chin Eng
authors.initials: CE
authors.lastname: Ong
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002934:Cinnamates / Q000737:chemistry; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D053630:Depsides / Q000737:chemistry; D006801:Humans; D031342:Orthosiphon / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D000097123:Rosmarinic Acid
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D002934:Cinnamates; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D053630:Depsides; D010936:Plant Extracts; D000097123:Rosmarinic Acid; C450260:CYP2C9 protein, human; C510163:CYP3A4 protein, human