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Mar. Drugs 2012, 10(1), 242-257; doi:10.3390/md10010242
Article

Fucoxanthin Attenuates Rifampin-Induced Cytochrome P450 3A4 (CYP3A4) and Multiple Drug Resistance 1 (MDR1) Gene Expression Through Pregnane X Receptor (PXR)-Mediated Pathways in Human Hepatoma HepG2 and Colon Adenocarcinoma LS174T Cells

1
, 2,3,†,*  and 1,†,*
1 Department of Food Science and Biotechnology, National Chung Hsing University, Taichung 402, Taiwan 2 Department of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan 3 Department of Emergency, Toxicology Center, China Medical University Hospital, Taichung 404, Taiwan These authors contributed equally to this work.
* Authors to whom correspondence should be addressed.
Received: 7 December 2011 / Revised: 10 January 2012 / Accepted: 16 January 2012 / Published: 23 January 2012
(This article belongs to the Special Issue Bioactive Compounds from Marine Sponges)
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Abstract

Pregnane X receptor (PXR) has been reported to regulate the expression of drug-metabolizing enzymes, such as the cytochrome P450 3A (CYP3A) family and transporters, such as multiple drug resistance 1 (MDR1). Fucoxanthin, the major carotenoid in brown sea algae, is a putative chemopreventive agent. In this study, we determined whether fucoxanthin could overcome drug resistance through attenuation of rifampin-induced CYP3A4 and MDR1 gene expression by PXR-mediated pathways in HepG2 hepatoma cells. We found that fucoxanthin (1–10 μM) significantly attenuated rifampin (20 μM)-induced CYP3A4, MDR1 mRNA and CYP3A4 protein expression at 24 h of incubation. Mechanistically, fucoxanthin strongly attenuated the PXR-mediated CYP3A4 promoter activity in HepG2 cells. In addition, fucoxanthin attenuated constitutive androstane receptor (CAR)- and rPXR-mediated CYP3A4 promoter activity in this cell line. Using the mammalian two-hybrid assay, we found that fucoxanthin significantly decreased the interaction between PXR and SRC-1, a PXR co-activator. Thus, fucoxanthin can decrease rifampin-induced CYP3A4 and MDR1 expression through attenuation of PXR-mediated CYP3A4 promoter activation and interaction between PXR and co-activator. These findings could lead to potentially important new therapeutic and dietary approaches to reduce the frequency of adverse drug reactions.
Keywords: fucoxanthin; PXR; CYP3A4; MDR1; drug resistance; rifampin fucoxanthin; PXR; CYP3A4; MDR1; drug resistance; rifampin
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Liu, C.-L.; Lim, Y.-P.; Hu, M.-L. Fucoxanthin Attenuates Rifampin-Induced Cytochrome P450 3A4 (CYP3A4) and Multiple Drug Resistance 1 (MDR1) Gene Expression Through Pregnane X Receptor (PXR)-Mediated Pathways in Human Hepatoma HepG2 and Colon Adenocarcinoma LS174T Cells. Mar. Drugs 2012, 10, 242-257.

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