Dietary zinc deficiency increases the methylbenzylnitrosamine-induced formation of O6-methylguanine in the esophageal DNA of the rat.

Abstract

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.