Esophageal microsomal metabolism of N-nitrosomethylbenzylamine in the zinc-deficient rat

Epidemiological studies in China suggest that dietary zinc deficiency and environmental exposure to N-nitrosamine carcinogens, such as N-nitrosomethylbenzylamine (NMBA), are among the factors associated with an increased incidence of esophageal carcinoma in humans. NMBA belongs to a class of nitrosamines which require activation by the cytochrome P-450-dependent mixed-function oxidases in order to be mutagenic. Rats maintained on a zinc-deficient diet exhibited an increased incidence of NMBA-induced esophageal carcinoma when compared to rats on a control diet. The increased tumor formation was associated with an alteration of the microsomal metabolism of NMBA. Weanling male Sprague-Dawley rats were raised on egg protein diets containing 2.3 ppm zinc (low zinc) or 50 ppm zinc (control zinc). Analysis of tissues revealed a rapid decline in the levels of zinc in serum and esophagi of the animals fed the low-zinc diet. Gastric and hepatic zinc content did not differ significantly between the animals fed the low-zinc diet and the animals fed the control zinc diet, even after 6 weeks. Microsomes were prepared from esophageal mucosa, livers, and forestomachs from weanling animals fed these diets for 3 weeks. The rate of formation of benzaldehyde from NMBA by esophageal mucosal microsomes prepared from the rats fed the low-zinc diet was nearly 10-fold higher than that of the rats fed the control zinc diet [0.230 +/- 0.047 (S.E.) versus 0.024 +/- 0.008 nmol/min/mg microsomal protein; p less than 0.001]. The rate of benzaldehyde formation by hepatic microsomes was 0.062 +/- 0.005 nmol/min/mg microsomal protein in the rats fed the low-zinc diet and 0.042 +/- 0.002 nmol/min/mg microsomal protein in the rats fed the control zinc diet (p less than 0.01). The rate of benzaldehyde formation by forestomach microsomes was not detectable in tissue from rats on either diet. This increased rate of NMBA metabolism by esophageal mucosal microsomes from the zinc-deficient rats may explain the increased incidence of esophageal carcinoma in these animals.