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 the 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 CYP1B1 as well as CYP1A1 expression, as evidenced by mRNA measurements. Cotreatment 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.
Footnotes
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This study was supported by grants from the National Institutes of Health (GM55561) and the Department of Defense (N6311602MD200 and GC-3532-03-42153CM). M.K. is an employee of the MatTek Corporation.
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This work was presented in part at the Experimental Biology 2005 meeting in San Diego CA, April 2–6, 2005: Walle T, Walle UK, Sedmera D, and Klausner M (2005) Transport of dietary polyphenols through the multilayer oral epithelium: implications for prevention of oral cancer. FASEB J19:A543.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.007948.
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ABBREVIATIONS: PAH, polycyclic aromatic hydrocarbon; BaP, benzo[a]pyrene; RT-PCR, reverse transcription-polymerase chain reaction.
- Received October 19, 2005.
- Accepted December 14, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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