title: Inhibitory effects of limonin on six human cytochrome P450 enzymes and P-glycoprotein in vitro.
abstract: Among the various possible causes for drug interactions, pharmacokinetic factors such as inhibition of drug-metabolizing enzymes and transporters, especially cytochrome P450 (CYP) isoenzymes and P-glycoprotein (P-gp), are regarded as the most frequent and clinically important. Limonin is a widely used dietary supplement and one of the most prevalent citrus limonoids, which are known to have inhibitory effects on CYPs and P-gp. In this study, the in vitro inhibitory effects of limonin on the major human CYP isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) activities in human liver microsomes were examined using liquid chromatography-tandem mass spectrometry. The inhibitory effects of limonin on P-gp activity in a human metastatic malignant melanoma cell line WM-266-4 were examined using a calcein-AM fluorometry screening assay. It demonstrates that limonin has negligible inhibitory effects on human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and P-gp. However, potent inhibition of CYP3A4 by limonin is observed with IC50 values of 6.20 μM (CYP3A4/testosterone) and 19.10 μM (CYP3A4/midazolam). This finding has important implications with regard to food-drug interactions between limonin and several narrow therapeutic index drugs that are metabolized by CYP3A4.
authors: The Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Yishan Road 600, Shanghai 200233, China.
authors: Yong-Long
authors: YL
authors: Han
authors: Hong-Liang
authors: HL
authors: Yu
authors: Dan
authors: D
authors: Li
authors: Xiang-Le
authors: XL
authors: Meng
authors: Zhi-Yong
authors: ZY
authors: Zhou
authors: Qi
authors: Q
authors: Yu
authors: Xiao-You
authors: XY
authors: Zhang
authors: Fu-Jing
authors: FJ
authors: Wang
authors: Cheng
authors: C
authors: Guo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D018565:Food-Drug Interactions; D006801:Humans; D036701:Limonins / Q000633:toxicity*; D008862:Microsomes, Liver; D053719:Tandem Mass Spectrometry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D036701:Limonins; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C001546:limonin