Metabolic Activation of Heterocyclic Amines and Expression of CYP1A1 in the Tongue

Abstract

Xenobiotic metabolism in oral tissues, especially in the tongue, has never been reported. In the present study, the metabolic activation/detoxification ability of promutagens in the tongue and the expression levels of related enzymes were investigated. Quantitative PCR analysis of rat tongue demonstrated constitutive messenger RNA (mRNA) expression of numerous drug-metabolizing enzymes. In particular, we detected mRNA, protein expression, and enzymatic activity of cytochrome P450 (CYP)1A1 in the tongue tissue. Metabolic activation of promutagens in the tongue was estimated using benzo[a]pyrene or heterocyclic amines (HCAs), found in cooked meat and tobacco products. Metabolic activation levels of HCAs in the tongue were comparable to those in the liver. In contrast, the expression levels of glutathione-S-transferase (GST) and uridine diphosphate-glucuronosyltransferase (UGT) in the tongue were considerably lower compared with those in the liver, and as a result, the mutagenic activity in the tongue was not decreased by GST- or UGT-dependent conjugation. Treatment of rats with sudan III, a typical inducer of CYP1A1, resulted in markedly increased CYP1A1 mRNA, protein expressions, and CYP1A-dependent enzymatic and mutagenic activities. In addition, CYP1A1 mRNA expression in carcinoma cells (SAS) was induced by sudan III exposure. In conclusion, mutagenic activation of xenobiotics and an increased risk of cancer in the tongue were observed in this study. Furthermore, ingestion of drug-metabolizing enzyme inducers has the potential to increase the metabolic activation in the tongue tissue and increase the risk of biomolecular attack by promutagens.

High expression of the mRNA of cytochrome P450 and phase II enzymes in the lung and kidney tissues of cattle

“…In line with this result, CYP1A1 protein was highly expressed in the bovine liver (Sivapathasundaram et al, 2001). In a previous report, the cattle liver also showed higher CYP1A1-dependent ethoxyresorufin O-deethylase activity compared with the rat liver (Darwish et al, 2010). Interestingly, other examined tissues, such as the lung, tongue and mammary glands, showed similar expression pattern to that observed in the liver.…”

“…The high expression of CYP1A1-like mRNA in the lungs and tongue corresponds to that reported by Darwish et al (2010b), who observed higher expression for CYP1A1-like mRNA in the lungs and tongue of camel. Takiguchi et al (2010) also observed high CYP1A1 mRNA and protein expression in the tongue of the rat. The relatively high expression of CYP1A-like mRNA in the mammary glands may be correlated to the occurrence of a remarkable rate of aflatoxin B1 hydroxylation to aflatoxin M1 in a clonal cell line established from primary bovine mammary epithelial cells as mentioned by Caruso et al (2009).…”

“…UGT1A1-like mRNA was expressed in all tissues examined, except for the mammary glands. Many UGT1 isoenzymes have also been expressed in extrahepatic tissues, including the kidney, stomach, small intestine, colon, tongue and many other tissues in rats and mice (Buckley and Klaassen, 200;Takiguchi et al, 2010). However, surprisingly in cattle, the kidney showed the highest expression pattern for UGT1A1 compared with the expression in the liver.…”

“…In many species, the liver shows the highest expression of these enzymes and other phase II enzymes, but these enzymes are also expressed in extrahepatic tissues, such as the kidney, intestine, lung and tongue (Darwish et al, 2010). We recently reported the unique expression pattern of CYP1A1, in particular in ungulates.…”

Sudan III dye strongly induces CYP1A1 mRNA expression in HepG2 cells

“…Previous studies have reported that Sudan dyes may increase the risk of DNA damage directly by the formation of DNA adducts and oxidation [1,2]. In addition, indirect effects via the enhancement of metabolic activation of chemicals have been suggested [3][4][5].…”