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Metabolism of N-Nitrosomethyl-n-amylamine by Microsomes from Human and Rat Esophagus¹

Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68198 [Q. H., J. N., S. S. M.]; Department of Pathology, Medical College of Ohio, Toledo, Ohio 43699 [G. S.]; and Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201 [J. R.]

Asymmetric dialkylnitrosamines induce esophageal cancer in rats and hence might be involved in the etiology of this cancer in humans. As a test of this hypothesis, we examined whether nitrosamines can be activated by segments of human esophagus and by microsomes of human and rat esophagus and liver. Specimens of 8 human esophagi were removed <6 h after death, and segments were incubated for 6 h with 23 and 300 µM N-nitrosomethyl-n-amylamine (NMAA). Hydroxy-NMAA yields were determined by gas chromatography-thermal energy analysis and were insignificant except for those of 5-hydroxy-NMAA, which were low. Microsomes were prepared from 4 batches of human esophagi and samples with 0.6 mg protein were incubated for 20 min with NMAA and cytochrome P-450 cofactors. We determined hydroxy-NMAAs as before and aldehydes by high-performance liquid chromatography of their 2,4-dinitrophenylhydrazones. Incubation of these microsomes with 12 mM NMAA yielded mean values of 0.64 nmol formaldehyde ("demethylation"), 0.21 nmol pentaldehyde ("depentylation"), and 0.56 nmol total hydroxy-NMAAs/min/mg protein. Metabolite yields under various conditions were determined, including a demonstration that carbon monoxide inhibited 81% of NMAA demethylation, indicating that cytochrome P-450 enzymes were involved. We also examined N-nitrosodimethylamine (NDMA) demethylation by the same microsomes. Rat esophageal microsomes dealkylated NMAA and NDMA similarly to human esophageal microsomes, but with 2–6 times and twice the activity, respectively. Human and rat esophageal microsomes demethylated 6 mM NMAA 18–20 times as rapidly as they demethylated 5 mM NDMA, in contrast to liver microsomes of these species, which demethylated 6 mM NMAA only 0.9–1.4 times as rapidly as they demethylated 5 mM NDMA. However, liver microsomes of both species were more active than esophageal microsomes for NMAA depentylation. The occurrence of NMAA demethylation and (to a lesser extent) depentylation with both human and rat esophageal microsomes is important because these are the activating reactions, and suggests that both human and rat esophagus contain P-450 isozymes that specifically dealkylate asymmetric dialkylnitrosamines.

¹ This work was supported by Grant R01 CA-35628 and Core Grant CA-36727 from the National Cancer Institute, Grant 92-33 from the Nebraska Department of Health, and Core Grant SIG-16 from the American Cancer Society. Some of the findings in this article were presented previously (1, 2).

² To whom requests for reprints should be addressed, at Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-6805.

Received 10/30/91. Accepted 4/24/92.

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