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

• Published in: Marine drugs Vol. 10; no. 1; pp. 242 - 257
• Main Authors: Liu, Cheng-Ling, Lim, Yun-Ping, Hu, Miao-Lin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.01.2012; MDPI
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Algae; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; Cell Line, Tumor; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; CYP3A4; Cytochrome; Cytochrome P-450 CYP3A - genetics; Drug resistance; fucoxanthin; Hep G2 Cells; Humans; Marine; MDR1; Pregnane X Receptor; Promoter Regions, Genetic; PXR; Receptors, Cytoplasmic and Nuclear - physiology; Receptors, Steroid - antagonists & inhibitors; Receptors, Steroid - physiology; rifampin; Rifampin - pharmacology; RNA, Messenger - analysis; Side effects; Transcriptional Activation; Xanthophylls - pharmacology; MDR1; PXR; drug resistance; CYP3A4; fucoxanthin; rifampin
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md10010242

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.