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Carcinogenesis Advance Access published online on July 8, 2006
Carcinogenesis, doi:10.1093/carcin/bgl118
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received February 3, 2006
Revised June 1, 2006
Accepted June 23, 2006

CANCER PREVENTION

Potent protective effect of isoimperatorin against aflatoxin B1-inducible cytotoxicity in H4IIE cells: bifunctional effects on glutathione S-transferase and CYP1A

Yuba Raj Pokharel 1, Eun Hee Han 1, Ji Young Kim 1, Soo Jin Oh 2, Sang Kyum Kim 2, Eun-Rhan Woo 1, Hye Gwang Jeong 1, and Keon Wook Kang 1 *

1 College of Pharmacy, Chosun University, Seosuk-dong, Dong-gu, Gwangju 501-759, South Korea
2 College of Pharmacy and Research Center for Transgenic Cloned Pigs, Chungnam National University, Daejeon, 305-764, South Korea

* To whom correspondence should be addressed.
Keon Wook Kang, E-mail: kwkang{at}chosun.ac.kr


  Abstract

Typically chemopreventive agents either induce phase II detoxifying enzymes or inhibit the CYPs that are required for the metabolism of carcinogens. In this study, we isolated a coumarin compound, isoimperatorin from Poncirus trifoliata Raf., and studied its protective effects against aflatoxin B1 (AFB1)-induced cytotoxicity in H4IIE cells. Isoimperatorin (> 0.3 µM) significantly inhibited the cytotoxic effect of AFB1. CDNB (1-chloro-2,4-dinitrobenzene; GST subtype-nonspecific) and NBD (7-chloro-4-nitrobenzo-2-oxa-1,3-diazole; GST{alpha} type-specific) assays revealed that isoimperatorin (0.3-3 µM) increased GST activity in a concentration-dependent manner. Western blot analyses using subtype-specific antibodies confirmed that GST{alpha} protein, but not GSTµ or GST{pi}, was induced in cells treated with isoimperatorin. Reporter gene analysis using an antioxidant response element (ARE) containing construct and subcellular fractionation assays revealed that GST{alpha} induction by isoimperatorin is associated with Nrf2/ARE activation. Moreover, ethoxyresorufin-O-deethylase assays showed that isoimperatorin (2 µM) completely inhibited 3-methylchoranthrene-inducible CYP1A activity. These results indicate that isoimperatorin from Poncirus trifoliata Raf. possesses a potent hepatoprotective effect against AFB1, presumably through the induction of GST{alpha} and the direct inhibition of CYP1A, and suggest that isoimperatorin should be considered a potential chemopreventive.

Keywords: aflatoxin B1; isoimperatorin; glutathione S-transferase; CYP1A.
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