Journal Article

Potent protective effect of isoimperatorin against aflatoxin B<sub>1</sub>-inducible cytotoxicity in H4IIE cells: bifunctional effects on glutathione <i>S</i>-transferase and CYP1A

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

in Carcinogenesis

Volume 27, issue 12, pages 2483-2490
ISSN: 0143-3334
Published online July 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl118
Potent protective effect of isoimperatorin against aflatoxin B1-inducible cytotoxicity in H4IIE cells: bifunctional effects on glutathione S-transferase and CYP1A

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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; GSTα 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 GSTα protein, but not GSTμ or GSTπ, was induced in cells treated with isoimperatorin. Reporter gene analysis using an antioxidant response element (ARE) containing construct and subcellular fractionation assays revealed that GSTα 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 GSTα and the direct inhibition of CYP1A, and suggest that isoimperatorin should be considered a potential chemopreventive.

Journal Article.  4633 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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