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Introduction
Bile acids have been implicated as causative agents in cancers of the gastrointestinal tract, including cancers of the stomach (1), small intestine (2), biliary tract (3) and colon (4). Bile acids themselves cannot induce tumors (5); however, their presence or absence in the colon has been demonstrated to be a strong determinant of tumor incidence (6). Bile acids are considered to lack the ability to initiate tumorigenesis mainly on the basis that they are unable to induce DNA damage directly; therefore, bile acids are hypothesized to promote colon tumorigenesis by affecting intracellular signaling (7). Cholestasis is reported to cause the intra-hepatic retention of potentially toxic bile acids, which causes liver injury and biliary fibrosis or cirrhosis (8). This has been observed in rats with sustained high levels of bile acids following the intravenous infusion of bile acids (9) and in bile duct-ligated rats (10). Oxidative stress induces DNA damage, which causes chromosomal aberrations associated with cell transformation (11). Since bile acids induce oxidative stress, they are thus considered potential carcinogens (12).
Cytochrome P450 (CYP) constitutes a superfamily of heme-containing enzymes that take part in the metabolism and elimination of various exogenous and endogenous substances (13,14). They play critical roles in the biotransformation of drugs, carcinogens, steroid hormones and environmental toxicants (15–17). CYP1A1 and CYP1A2 catalyze the oxygenation of polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines/amides (HAAs) (18). Changes in the levels of CYPs may contribute to the development of cancer (13). PAHs induce CYP1A via the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. When PAHs bind to AhR, sequential signaling events are initiated that activate the AhR and induce transcription of CYP1A genes through the xenobiotic response element (XRE) located in the enhancers of the genes (19).
Humans are exposed to PAHs and HAAs from a wide range of sources, including tobacco smoke, automobile exhaust, smoked and cooked food and industrial processes. Such exposure has been causatively linked to an increased incidence of cancers in smokers and certain other populations (20). One of the most well-characterized molecular responses to PAHs is the induction of the CYP1A1 gene, which encodes the carcinogen-activating enzyme CYP1A1 (21). Moreover, chemicals present in the diet can activate AhRs; several dietary plant compounds have been reported to competitively...