Dibenzoylmethane Activates Nrf2-Dependent Detoxification Pathway and Inhibits Benzo(a)pyrene Induced DNA Adducts in Lungs

R.   K.   Thimmulappa; T.      Rangasamy; J.      Alam; S.      Biswal

Abstract

Cigarette smoke derived carcinogens have been identified as the main agents implicated in lung carcinogenesis. Epidemiological as well as animal studies have indicated that certain phytochemicals can block the carcinogenic process by enhancing the detoxification of environmental and or dietary carcinogens. Dibenzoylmethane (DBM), a minor constituent of licorice, is a beta-ketone analog of curcumin, a promising chemopreventive agent for colon, breast and skin cancer. The present study was designed to examine the chemopreventive efficacy of DBM in lungs, its global molecular targets and the mechanism of its action. Feeding DBM to A/J mice significantly inhibited benzo[a]pyrene induced DNA adducts in lungs. Further analysis of its global molecular targets in lungs by oligonucleotide microarray revealed expression of several cytoprotective genes including phase II enzymes that are regulated by Nrf2, a basic leucine zipper transcription factor. To decipher if DBM mediates its function via Nrf2 activation, Nrf2 dependent reporter assays were performed. DBM elicited a dose-dependent increase in antioxidant response element (ARE)-driven luciferase reporter activity which correlated with an increase in mRNA expression of NQO1, GSTA2, and GCLC in mouse hepatoma cells, which are well established targets of Nrf2. Conversely, DBM stimulated ARE reporter activity was attenuated by a dominantnegative mutant of Nrf2. Electrophoretic mobility shift assay confirmed that DBM greatly increased the DNA binding activity of Nrf2. In conclusion, DBM mediates the induction of phase II enzymes by Nrf2 activation and inhibits benzo[a]pyrene induced DNA adducts by enhancing its detoxification in lungs.

Keywords: Dibenzoylmethane, Nrf2, Benzo(a)pyrene, A/J mice, lung, Phase II enzymes, DNA adducts

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