CHARACTERIZATION OF XENOBIOTIC-METABOLIZING ENZYMES AND NITROSAMINE METABOLISM IN THE HUMAN ESOPHAGUS

Esophageal cancer has been associated with tobacco smoking, and nitros amines are possible causative agents for this cancer. The present stud y investigated the metabolism of the tobacco carcinogens N'-nitrosonor nicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and N-nitrosodimethylamine (NDMA), as well as the presence of xenobiot ic-metabolizing enzymes in human esophageal tissues from individuals i n the United States and Huixian, Henan Province, China (a high-risk ar ea for esophageal cancer). All esophageal microsomal samples activated NNN and the metabolic rate was 2-fold higher in the esophageal sample s from China than the USA. All microsomal samples activated NDMA, Howe ver, most of the microsomal samples did not activate NNK. Troleandomyc in tan inhibitor of cytochrome P450 3A) decreased the formation of NNN -derived keto acid by 20-26% in the esophageal microsomes. The activit ies for NADPH: cytochrome c reductase, ethoxycoumarin O-deethylase, NA D(P)H: quinone oxidoreductase and glutathione S-transferase were prese nt in the esophageal samples. Coumarin 7-hydroxylase (a representative activity for P450 2A6) activity was not detected in the esophageal mi crosomal samples. The activities for nitrosamine metabolism and xenobi otic-metabolizing enzymes were decreased (by 30-50%) in the squamous c ell carcinomas compared with their corresponding non-cancerous mucose. The presence of activation and detoxification enzymes in the esophagu s may play an important role in determining the susceptibility of the esophagus to the carcinogenic effect of nitrosamines, Our results sugg est that P450s 3A4 and 2E1 are involved in the activation of NNN and N DMA, respectively, in the human esophagus.