Esophageal and Hepatic Microsomal Metabolism of N-nitrosomethylbenzylamine and N-nitrosodimethylamine in the Rat

The metabolism of the rat esophageal carcinogen N-nitrosomethylbenzylamine (NMBzA) was studied using microsomes prepared from liver and esophageal mucosa of untreated male Sprague-Dawley rats. NMBzA was extensively metabolized to benzaldehyde, benzyl alcohol, and formaldehyde by hepatic microsomes. The rate of metabolism at the benzyl moiety was 10-fold higher than that at the methyl moiety. Mucosal microsomes metabolized NMBzA to benzaldehyde and formaldehyde at rates one-fifth and one-sixtieth of those in the liver, respectively; benzyl alcohol formation was undetectable. Esophageal metabolism of NMBzA was exclusively located in the mucosa, preferentially in the microsomal fraction, was reduced nicotinamide adenine dinucleotide phosphate dependent, and was inhibited by CO and 2-diethylaminoethyl-2,2-diphenylvalerate. A low level of cytochrome P-450 was detected in the mucosal microsomes. Whereas hepatic metabolism of NMBzA was inducible by phenobarbitone pretreatment, mucosal metabolism was not altered by either phenobarbitone or 3-methylcholanthrene pretreatment. The hepatocarcinogen N-nitrosodimethylamine was extensively metabolized by hepatic microsomes to formaldehyde, but demethylation was not detected in the microsomes from esophageal mucosa, a nontarget tissue. The results indicate that rat esophageal mucosa contains an enzyme system which metabolizes NMBzA at a high rate and exhibits properties typical of cytochrome P-450. This enzyme may play a role in determining which compounds induce tumors in rat esophagus.