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Carcinogenesis Advance Access published online on July 6, 2005
Carcinogenesis, doi:10.1093/carcin/bgi173
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received March 24, 2005
Revised June 17, 2005
Accepted June 28, 2005

CARCINOGENESIS

Permeation and reservoir formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (BAP) across porcine esophageal tissue in the presence of ethanol and menthol

Chadi Azzi 1, Jin Zhang 1, Carryn H. Purdon 1, James M. Chapman 1, Daniela Nitcheva 2, James R. Hebert 3, and Eric W. Smith 1*

1 College of Pharmacy, University of South Carolina, Columbia, SC 29208
2 Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208; South Carolina Cancer Center, Columbia, SC 29203
3 Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208; South Carolina Statewide Cancer Prevention and Control Program, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425

* To whom correspondence should be addressed.
Eric W. Smith, E-mail: esmith{at}cop.sc.edu


  Abstract

Environmental influences may affect carcinogen absorption and residency in the tissues of the aero-digestive tract. We quantified the effect of ethanol and menthol on the rates of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (BAP) absorption using a fully validated in vitro diffusion system, capable of accurately and precisely quantifying tobacco carcinogen permeation and reservoir formation in porcine esophageal mucosa. Confocal microscopy was employed to visualize the location of BAP in the exposed membranes. Markedly different extents of permeation and reservoir formation for the tobacco carcinogens were recorded in the presence of ethanol and menthol. The water-soluble NNK permeated the membrane rapidly, while the lipophilic BAP did not appreciably diffuse through the tissue. Significantly different extents of reservoir formation were observed for the different carcinogens, and in the presence of the different penetration-enhancer solvents. Alcohol (at 5% concentration) did not influence the permeation or reservoir formation of NNK. A mentholated donor solution (0.08%) both decreased the flux of NNK and significantly increased the tissue reservoir formation. The magnitude of the reservoir formed by BAP was relatively extensive (even though membrane permeation rates were negligible), being greatest in the presence of both ethanol and menthol. This suggests synergy between the two penetration-enhancer species acting on this carcinogen. Confocal microscopy studies confirmed that there was an appreciable intra-cellular, and specifically nuclear, association of the BAP species during the reservoir formation process. The aqueous solubility of the diffusing species and the presence of penetration enhancers appeared to be key factors in the absorption and cellular binding processes. The results presented support the hypothesis that the use of mentholated cigarettes, or the concomitant consumption of alcohol while smoking, may have marked effects on the fate of tobacco chemicals. This finding may help to explain elevated rates of esophageal squamous cell carcinoma in African Americans.


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