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Drug Metabolism and Disposition Fast Forward
First published on December 28, 2005; DOI: 10.1124/dmd.105.007948

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Received for publication October 19, 2005.
Revised December 8, 2005.
Accepted for publication December 14, 2005.

Benzo[a]pyrene-induced oral carcinogenesis and chemoprevention - studies in bioengineered human tissue

Thomas Walle 1*, U. Kristina Walle 1, David Sedmera 1, Mitch Klausner 2

1 Medical University of South Carolina 2 MatTek Corporation

* Address correspondence to: E-mail: wallet{at}musc.edu

Abstract

Oral cancer, originating from smoking-induced lesions of the basal cells in the complex stratified oral epithelium, is difficult to treat. Early detection of premalignant lesions, e.g., leukoplakia, has suggested the possibility of chemopreventive measures, such as topical application of antimutagenic/antiproliferative dietary or pharmaceutical agents. As an extension of a study in human oral epithelial cell monolayers, we determined carcinogen, i.e. benzo[a]pyrene (BaP), transport, bioactivation and DNA binding in a bioengineered human gingival epithelial tissue construct and the chemopreventive effects of dietary polyphenols. Short-term experiments showed that both types of compounds can traverse this tissue as well as be effectively taken up by the tissue. The model cigarette smoke carcinogen BaP very slowly, but to a great extent, accumulated in the tissue with maximal uptake at 24 h. Such exposure clearly resulted in DNA binding of BaP by the tissue. This DNA binding was associated with BaP-induced cytochrome P450 (CYP) 1B1 as well as CYP1A1 expression, as evidenced by mRNA measurements. Co-treatment of the oral tissue with dietary polyphenols, including resveratrol and quercetin, and BaP, resulted in significant inhibition of the BaP-DNA binding. Using fluorescence microscopy as well as simultaneous autoradiography, we also demonstrated that quercetin indeed penetrates the entire stratified tissue layer, but that quercetin was also oxidized within the cells. Thus, this bioengineered oral tissue construct opens up improved ways of understanding and preventing/treating smoking-induced oral cancer.


Key words: absorption, bioactivation, bioavailability, carcinogen metabolism, carcinogenesis, chemoprotection, CYP1A, CYP1B, DNA binding, oral absorption


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[Abstract] [Full Text] [PDF]


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