Dietary 5-demethylnobiletin modulates xenobiotic-metabolizing enzymes and ameliorates colon carcinogenesis in benzo[a]pyrene-induced mice
Journal
Food and Chemical Toxicology
Journal Volume
155
Date Issued
2021
Author(s)
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. ? 2021 Elsevier Ltd
Subjects
5-Demethylnobiletin (5-DMNB)
Benzo[a]pyrene (BaP)
Colon cancer
Xenobiotic-metabolizing enzymes
5 demethylnobiletin
antineoplastic agent
benzo[a]pyrene
cytochrome P450 1B1
glucuronosyltransferase
glutathione transferase
tumor necrosis factor
unclassified drug
5-demethylnobiletin
antiinflammatory agent
Cyp1b1 protein, mouse
dextran sulfate
flavone derivative
animal experiment
animal model
animal tissue
antineoplastic activity
Article
biotransformation
colon cancer
colon carcinogenesis
controlled study
detoxification
drug determination
drug effect
drug structure
enzyme activity
gene expression
male
mouse
nonhuman
protein expression
protein function
upregulation
animal
Bagg albino mouse
carcinogenesis
colon
colon tumor
Hep-G2 cell line
human
Institute for Cancer Research mouse
metabolism
pathology
Animals
Anti-Inflammatory Agents
Anticarcinogenic Agents
Benzo(a)pyrene
Carcinogenesis
Colon
Colonic Neoplasms
Cytochrome P-450 CYP1B1
Dextran Sulfate
Flavones
Glucuronosyltransferase
Glutathione Transferase
Hep G2 Cells
Humans
Male
Mice, Inbred BALB C
Mice, Inbred ICR
SDGs
Type
journal article