Dietary 5-demethylnobiletin modulates xenobiotic-metabolizing enzymes and ameliorates colon carcinogenesis in benzo[a]pyrene-induced mice

Abstract

The intake of common polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), is strongly correlated to the initiation of colon cancer. BaP is a well-known pro-carcinogen that is metabolically activated by xenobiotic-metabolizing enzymes. Studies indicate that polymethoxyflavones, including 5-demethylnobiletin (5-DMNB), exhibit anti-inflammatory and anti-carcinogenic properties. However, the effects of 5-DMNB on xenobiotic-metabolizing enzymes and BaP-induced carcinogenesis remain unclear. The combination of BaP and a promoting agent-dextran sulfate sodium (DSS)-has been demonstrated to induce tumors in mouse models. Thus, this study aimed to determine the protective effect of 5-DMNB on carcinogen biotransformation and BaP/DSS-induced colon carcinogenesis. Our results showed that 5-DMNB had a substantial inhibitory effect on CYP1B1 induced by BaP and upregulated the detoxification enzymes UDP-glucuronosyltransferases (UGTs) and glutathione S-transferases (GSTs). Furthermore, subsequent analyses confirmed that the dietary administration of 5-DMNB markedly ameliorated tumor formation in BaP/DSS-treated mice. Exposure to BaP/DSS also significantly elevated TNF-α levels, and the administration of 5-DMNB reversed this increase. Taken together, we determined that 5-DMNB attenuates BaP/DSS-induced colon cancer through the regulation of inflammation and xenobiotic-metabolizing enzymes. These results indicate that 5-DMNB has significant potential as a novel chemopreventive agent for preventing carcinogen activation and inflammation-associated carcinogenesis.

Keywords: 5-Demethylnobiletin (5-DMNB); Benzo[a]pyrene (BaP); Colon cancer; Xenobiotic-metabolizing enzymes.