Characterization of xenobiotic-metabolizing enzymes and nitrosamine metabolism in the human esophagus

Esophageal cancer has been associated with tobacco smoking, andnitrosamines are possible causative agents for this cancer. The presentstudy investigated the metabolism of the tobacco carcinogens N'-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone(NNK), and N-nitrosodimethylamine (NDMA), as well as the presence ofxenobiotic-metabolizing enzymes in human esophageal tissues fromindividuals in the United States and Huixian, Henan Province, China (ahigh-risk area for esophageal cancer). All esophageal microsomal samplesactivated NNN and the metabolic rate was 2-fold higher in the esophagealsamples from China than the USA. All microsomal samples activated NDMA.However, most of the microsomal samples did not activate NNK.Troleandomycin (an inhibitor of cytochrome P450 3A) decreased the formationof NNN-derived keto acid by 20-26% in the esophageal microsomes. Theactivities for NADPH: cytochrome c reductase, ethoxycoumarin O-deethylase,NAD(P)H: quinone oxidoreductase and glutathione S-transferase were presentin the esophageal samples. Coumarin 7-hydroxylase (a representativeactivity for P450 2A6) activity was not detected in the esophagealmicrosomal samples. The activities for nitrosamine metabolism andxenobiotic- metabolizing enzymes were decreased (by 30-50%) in the squamouscell carcinomas compared with their corresponding non-cancerous mucosa. Thepresence of activation and detoxification enzymes in the esophagus may playan important role in determining the susceptibility of the esophagus to thecarcinogenic effect of nitrosamines. Our results suggest that P450s 3A4 and2E1 are involved in the activation of NNN and NDMA, respectively, in thehuman esophagus.