7-methylguanine and Esophageal-Neoplasms

An immunohistochemical method, followed by silvering (Ag-treatment) of the final product of peroxidase reaction for N7-methylguanine detection, was first employed for human cells treated in vitro with N-methylnitrosourea. This method appeared to be highly specific and sensitive, compared to the routine immunohistochemical technique. Evidence has been provided on the application of Ag-treatment for detecting N7-methylguanine in the esophagus epithelium of patients with a high risk of cancer with this particular locality.

Topics: China; Disease Reservoirs; DNA; Epithelial Cells; Epithelium; Esophageal Neoplasms; Esophagus; Guanine; Humans; Immunohistochemistry; Intestinal Mucosa; Intestines; Methylnitrosourea; Sensitivity and Specificity; Silver Staining

Dietary zinc deficiency in combination with environmental exposure to methylbenzylnitrosamine (MBN) is associated with an increased incidence of esophageal carcinoma in man. The proposed mechanism of MBN-induced esophageal carcinoma is through metabolic activation of MBN to form benzaldehyde, and a carbonium ion which methylates DNA. MBN is known to methylate DNA forming O6-methylguanine (O6-MeG) adducts. These adducts can induce guanine to adenine point mutations and such mutations are responsible for certain carcinogen-induced tumors. Rats maintained on a zinc-deficient diet exhibit an increased incidence of MBN-induced esophageal carcinoma when compared with ad libitum and pair-fed controls. The caloric restriction of the pair-fed controls was associated with a lower incidence of MBN-induced esophageal carcinoma than was observed in the ad libitum controls. These differences in tumor incidence were associated with alterations in the formation and clearance of MBN-induced esophageal O6-MeG. Weanling male Sprague-Dawley rats were raised on egg protein diets containing 2.3 p.p.m. zinc (low zinc) or 50 p.p.m. zinc (control). One group of control animals was fed the control diet ad libitum and a second group pair-fed the control diet to match the intake of the zinc-deficient group. After 3 weeks on the diets the animals were injected with a single dose of MBN (2.0 mg/kg b.w.) and levels of esophageal O6-MeG were determined after 1, 3, 6 and 24 h. O6-MeG was significantly higher in the zinc-deficient animals than in controls, with the pair-fed controls demonstrating O6-MeG levels lower than the ad libitum controls. Thus, dietary zinc deficiency results in significantly increased levels of MBN-induced esophageal O6-MeG, and caloric restriction results in decreased levels of MBN-induced esophageal O6-MeG. These changes in esophageal O6-MeG may in part explain the increased incidence of MBN-induced esophageal carcinoma observed with dietary zinc deficiency.

Topics: Animals; Deficiency Diseases; Dimethylnitrosamine; DNA; Esophageal Neoplasms; Esophagus; Guanine; Male; Mutation; Rats; Rats, Inbred Strains; Zinc

Several O6-alkylGua adducts have been shown to be removed from DNA during its repair by transfer of the alkyl group to a cysteine residue in a specific AAP, with the formation of S-alkylcysteine. As the reaction is stoichiometric and irreversible, the AAP content of the cell can be reduced or depleted. In vivo depletion by a high dose of nitrosamine can be used to test for the formation of a repairable alkylation adduct at the O6-position of guanine. In addition, if the carcinogenic potency of a nitroso compound for a particular organ is related to the persistence of the adduct in DNA, potency would depend not on the level of alkylation attained after treatment, but on whether this was sufficient to deplete the AAP content of the organ concerned and so to slow down repair, i.e. depletion of AAP is a more relevant estimate of potency than is the initial extent of DNA alkylation. Dose-response studies on target and non-target organs showed that depletion of AAP correlated with organotropy for those nitrosamines known to methylate DNA, i.e. with NDMA for liver, and with NMBzA for oesophagus. With NDEA, the results supported the suggestion that other adducts in addition to O6-alkylGua may be involved. NMPhA, an oesophageal specific carcinogen, did not deplete AAP in oesophagus, and induced AAP in liver. This result adds to the evidence that NMPhA does not alkylate DNA.

Topics: Alkylation; Animals; Cysteine; Dimethylnitrosamine; DNA; DNA Repair; DNA Replication; Esophageal Neoplasms; Esophagus; Guanine; Liver; Liver Neoplasms, Experimental; Methyltransferases; Nitrosamines; O(6)-Methylguanine-DNA Methyltransferase; Protein Biosynthesis; Rats; Rats, Inbred Strains