Characterization of xenobiotic-metabolizing enzymes and nitrosamine metabolism in the human esophagus.
Esophageal cancer has been associated with tobacco smoking, and nitrosamines are possible causative agents for this cancer. The present study 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 of xenobiotic-metabolizing enzymes in human esophageal tissues from individuals in the United States and Huixian, Henan Province, China (a high-risk area for esophageal cancer). All esophageal microsomal samples activated NNN and the metabolic rate was 2-fold higher in the esophageal samples 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 formation of NNN-derived keto acid by 20-26% in the esophageal microsomes. The activities for NADPH: cytochrome c reductase, ethoxycoumarin O-deethylase, NAD(P)H: quinone oxidoreductase and glutathione S-transferase were present in the esophageal samples. Coumarin 7-hydroxylase (a representative activity for P450 2A6) activity was not detected in the esophageal microsomal samples. The activities for nitrosamine metabolism and xenobiotic-metabolizing enzymes were decreased (by 30-50%) in the squamous cell carcinomas compared with their corresponding non-cancerous mucosa. The presence of activation and detoxification enzymes in the esophagus may play an important role in determining the susceptibility of the esophagus to the carcinogenic effect of nitrosamines. Our results suggest that P450s 3A4 and 2E1 are involved in the activation of NNN and NDMA, respectively, in the human esophagus.
Smith
T J
TJ
Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, NJ 08855, USA. tjsmith@rci.rutgers.edu
Liao
A
A
Wang
L D
LD
Yang
G Y
GY
Starcic
S
S
Philbert
M A
MA
Yang
C S
CS
D000328:Adult; D004128:Dimethylnitrosamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004798:Enzymes / Q000378:metabolism*; D004947:Esophagus / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D009602:Nitrosamines / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D004798:Enzymes; D009602:Nitrosamines; D015262:Xenobiotics; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D004128:Dimethylnitrosamine; C008655:N'-nitrosonornicotine