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.
Highlights
Fucoxanthin, the major non-provitamin A carotenoid found in Undaria Pinnatifida, has been shown to have many biological functions, such as suppression of adipocyte differentiation [1], anti-mutagenicity [2], anti-inflammation [3], and anti-cancer effects
We found that fucoxanthin (1–10 μM) significantly decreased the basal CYP3A4 mRNA
We found that fucoxanthin (1–10 μM) significantly decreased the basal expression of multiple drug resistance 1 (MDR1)
Summary
Fucoxanthin, the major non-provitamin A carotenoid found in Undaria Pinnatifida, has been shown to have many biological functions, such as suppression of adipocyte differentiation [1], anti-mutagenicity [2], anti-inflammation [3], and anti-cancer effects. Studies have shown that fucoxanthin exhibits anti-proliferative potential by inducing cell cycle arrest at the G0/G1 phase and apoptosis of various cell lines, such as prostate cancer PC-3, DU 145, and LNCaP cells [4], leukemia. Fucoxanthin can be hydrolyzed into fucoxanthinol by lipase, cholesterol esterase, carboxylesterase in intestinal Caco-2 cells and in mice [7] subsequently converted into amarouciaxanthin a, which is a major metabolite of fucoxanthin in the liver of mice [8]. A lot of evidence indicates that phytochemicals found in fruit and vegetables exhibit chemoprevention and anti-drug resistance potential. Curcumin [10], epigallocatechin-3-gallate (EGCG) [11]
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