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Carcinogenesis Advance Access published online on March 4, 2008
Carcinogenesis, doi:10.1093/carcin/bgn064
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dietary curcumin modulates transcriptional regulator(s) of phase I and phase II enzymes in benzo(a)pyrene-treated mice: mechanism of its anti-initiating action

Rachana Garg, Sanjay Gupta and Girish Maru*

Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai-410 208, India

* To whom correspondence should be addressed. Tel: 91-22-27405022; Fax: 91-22-27405085; E-mail: gmaru{at}actrec.gov.in

Curcumin has been shown to possess anti-initiating and anti-promoting activity in experimental systems. However, the mechanism(s) of its action(s) are not fully elucidated in vivo. In the present study mechanism(s) of curcumin-mediated anti-initiation were investigated in mice employing benzo(a)pyrene (B[a])P) as a model carcinogen. Dietary pre-treatment of mice with chemopreventive doses of curcumin showed significant inhibition of B(a)P-induced enzyme activity, protein and mRNA levels of cytochrome P450 1A1/1A2 in liver and lungs. Although curcumin alone did not alter the basal levels of aryl hydrocarbon receptor (AhR), it significantly decreased the B(a)P-induced AhR protein levels, its phosphorylation, nuclear translocation and subsequent binding to DNA thereby decreasing the transactivation of CYP1A. Dietary curcumin led to increase in NF-E2-related factor-2 (Nrf2) protein levels and enhanced its nuclear translocation in liver and lungs of mice as compared to controls. Additionally, increased binding of Nrf2 to antioxidant response element (ARE) occurred in nuclear extracts from liver and lungs of mice pre-treated with dietary curcumin. Induction of activity, protein and mRNA levels of glutathione-S-transferase (GST), its isoforms and NAD(P)H:quinone oxidoreductase-1 (NQO1) by dietary curcumin in mice paralleled the curcumin-mediated activation of Nrf2, leading to increased detoxification of B(a)P. In agreement with the observed curcumin-mediated decrease in B(a)P-induced phase I enzyme and concomitant induction of phase II enzymes, pre-treatment with dietary curcumin resulted in significant reduction of B(a)P-induced DNA adduct, oxidative damage and inflammation. To conclude, curcumin exhibits anti-initiating effects via modulating the transcriptional regulator(s) of phase I and phase II enzymes in mice.

Received December 21, 2007; revised February 8, 2008; accepted February 27, 2008.


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