Carcinogenesis, Vol. 20, No. 5, 825-836,
May 1999
© 1999 Oxford University Press
Diffusion of dialkylnitrosamines into the rat esophagus as a factor in esophageal carcinogenesis
1 Eppley Institute for Research in Cancer,
2 Department of Pharmaceutical Sciences, College of Pharmacy,
3 Department of Pathology and
4 Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA and
5 Department of Biological Systems Engineering, School of Engineering, University of Nebraska-Lincoln, Lincoln, NE 68583-0726, USA
To indicate how readily nitrosamines (NAms) diffuse into the esophagus, we measured diffusion rate (flux) through rat esophagus of dialkyl-NAms using side-by-side diffusion apparatuses. Mucosal and serosal flux at 37°C of two NAms, each at 50 µM, was followed for 90 min by gas chromatography–thermal energy analysis of NAms in the receiver chamber. Mucosal flux of one or two NAms at a time gave identical results. Mucosal flux was highest for the strong esophageal carcinogens methyl-n-amyl-NAm (MNAN) and methylbenzyl-NAm. Mucosal esophageal flux of 11 NAms was 18–280 times faster and flux of two NAms through skin was 13–28 times faster than that predicted for skin from the molecular weights and octanol:water partition coefficients, which were also measured. Mucosal: serosal flux ratio was correlated (P < 0.05) with esophageal carcinogenicity and molecular weight. For seven NAms tested for carcinogenicity by Druckrey et al. [(1967) Z. Krebsforsch., 69, 103–201], mucosal flux was correlated with esophageal carcinogenicity with borderline significance (P = 0.07). The MNAN:dipropyl-NAm ratio for mucosal esophageal flux was unaffected when rats were treated with phenethylisothiocyanate and was similar to that for forestomach, indicating no involvement by cytochromes P450. Mucosal esophageal flux of MNAN and dimethyl-NAm was reduced by >90% on enzymic removal of the stratum corneum, was unaffected by 0.1 mM verapamil and was inhibited 67–94% by 1.0 mM KCN and 82–93% by 0.23% ethanol. NAm flux through rat skin and jejunum was 5–17% of that through esophagus. Flux through skin increased 5–13 times after enzymic or mechanical removal of the epidermis; the histology probably explained this difference from esophagus. Hence, NAms could be quite rapidly absorbed by human esophagus when NAm-containing foods or beverages are swallowed, the esophageal carcinogenicity of NAms may be partly determined by their esophageal flux and NAm flux probably occurs by passive diffusion.
Abbreviations: DEN, diethylnitrosamine; DMN, dimethylnitrosamine; DPN, dipropylnitrosamine; EC, esophageal papillomas and carcinomas; ER, endoplasmic reticulum; GC, gas chromatography; MBZN, methylbenzylnitrosamine; MNAN, methyl-n-amylnitrosamine; MPN, methylpropylnitrosamine; NAm, nitrosamine; NNN, N'-nitrosonornicotine; PC, partition coefficient (octanol:water unless mentioned otherwise); PEITC, phenethylisothiocyanate; TEA, thermal energy analysis.
6 To whom correspondence should be addressed Email: smirvish{at}unmc.edu
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