Toxicology in vitro : an international journal published in association with BIBRA

Inhibitory effects of limonin on six human cytochrome P450 enzymes and P-glycoprotein in vitro.

PMID 22001672


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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Limonin, from citrus seeds, >90% (HPLC)