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BENZO[A]PYRENE-INDUCED ORAL CARCINOGENESIS AND CHEMOPREVENTION – STUDIES IN BIOENGINEERED HUMAN TISSUE.
Walle1, T., Walle1, U.K., Sedmera2, D., Klausner3, M.
1Department of Cell and Molecular Pharmacology and Experimental Therapeutics, University of South Carolina, Charleston; 2Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston; 3MatTek Corporation, Ashland, Massachusetts.
Drug Metabolism and Disposition, 2006 34: 346-350.
Keywords: Antimutagenic agents, Antiproliferative agents, Benzo[α]pyrene, Buccal tissue, CYP, Carcinogenesis, Chemoprevention, Cigarette smoke carcinogen, Cytochrome P450, DMSO, Ellagic acid, EpiOral, Leukoplakia, Mannitol, Oral cancer, Oral epithelium, PAH, Paracellular transport marker, Permeability, Polycyclic aromatic hydrocarbons, Polyphenols, Quercetin, Resveratrol, Transepithelial transport
Endpoints: Autorardiography, Cytochrome P450, DNA binding, Fluorescence microscopy, Permeablity
Materials Tested: Benzo[α]pyrene, Ellagic Acid, Mannitol, Resveratrol
Summary:
Oral cancer, originating from smoking-induced lesions of the basal cells in the complex stratified oral epithelium, is difficult to treat. Early detection of pre-malignant 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, researchers at the University of South Carolina and the Medical University of South Carolina (USA) determined carcinogen, i.e. benzo[a]pyrene (BaP), transport, bioactivation and DNA binding in EpiGingival, 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 BaPDNA 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, the EpiGingival bioengineered oral tissue construct opens up improved ways of understanding and preventing/ treating smoking-induced oral cancer.
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