Epidemiological studies have identified dietary zinc deficiency, methylbenzyl-nitrosamine (MBN) and ethanol as factors associated with an increased incidence of esophageal carcinoma in man. Animals models have confirmed that dietary zinc deficiency and chronic consumption of ethanol increase the incidence of MBN- induced esophageal carcinoma. The proposed mechanism of nitrosamine induced carcinogenesis is viewed as a complex process involving metabolic activation of the carcinogen, detoxification of the carcinogen or its activated metabolites, chemical modification of cellular constituents, including DNA, and repair of critical cellular damage. The postulated mechanism of MBN- induced esophageal carcinogenesis is through oxidation of MBN to form benzaldehyde, and an activated metabolite which methylates DNA. MBN is known to methylate DNA forming 06-methylguanine adducts, and it is proposed that these adducts induce DNA point mutations which lead to cancer. Our previous studies have examined a number of steps in this schema. These studies have demonstrated that dietary zinc deficiency results in a significant increase in the cytochrome P-450 dependent esophageal microsomal metabolism of MBN, and a similar increase in the MBN-induced formation of esophageal 06-methylguanine. More recently we have demonstrated that our MBN-induced tumors are associated with inactivation of the ras oncogene. Examination of the amino acid substitutions in the ras p21 protein suggests that this activation is compatible with 06-methylguanine induced mutations. The mechanism of this increase in MBN activation, as well as the role of 06-methylguanine in the activation of the ras oncogene remains to be determined. This study proposes to identify which cytochrome P-450 isozymes activate and degrade MBN, to determine which factors alter the esophageal repair of 06-methylguanine, and by identification of the nucleotide mutations responsible for activation of the ras oncogene, to clarify the genetic mechanisms of MBN-induced mutagenesis. A better understanding of the mechanisms by which dietary factors increase the incidence of esophageal carcinoma may assist in the prevention and treatment of human carcinoma.
| Barch, D H; Rundhaugen, L M; Pillay, N S (1995) Ellagic acid induces transcription of the rat glutathione S-transferase-Ya gene. Carcinogenesis 16:665-8 |
