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.
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Authors | Yong-Long Han, Hong-Liang Yu, Dan Li, Xiang-Le Meng, Zhi-Yong Zhou, Qi Yu, Xiao-You Zhang, Fu-Jing Wang, Cheng Guo |
Journal | Toxicology in vitro : an international journal published in association with BIBRA
(Toxicol In Vitro)
Vol. 25
Issue 8
Pg. 1828-33
(Dec 2011)
ISSN: 1879-3177 [Electronic] England |
PMID | 22001672
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 Elsevier Ltd. All rights reserved. |
Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 Enzyme Inhibitors
- Enzyme Inhibitors
- Limonins
- Cytochrome P-450 Enzyme System
- Cytochrome P-450 CYP3A
- CYP3A4 protein, human
- limonin
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(metabolism)
- Cell Line, Tumor
- Chromatography, High Pressure Liquid
- Cytochrome P-450 CYP3A
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Enzyme System
(metabolism)
- Enzyme Inhibitors
(toxicity)
- Food-Drug Interactions
- Humans
- Limonins
(toxicity)
- Microsomes, Liver
- Tandem Mass Spectrometry
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