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Carcinogenesis Advance Access originally published online on July 8, 2006
Carcinogenesis 2006 27(12):2483-2490; 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

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

Yuba Raj Pokharel, Eun Hee Han, Ji Young Kim, Soo Jin Oh1, Sang Kyum Kim1, Eun-Rhan Woo, Hye Gwang Jeong* and Keon Wook Kang*

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

*To whom correspondence should be addressed Email: kwkang{at}chosun.ac.kr or hgjeong{at}chosun.ac.kr

Typically chemopreventive agents either induce phase II detoxifying enzymes or inhibit the cytochrome P450 enzymes (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; glutathine S-transferase (GST) subtype-non-specific] 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.


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