title: Clinical and biochemical studies support smokeless tobacco's carcinogenic potential in the human oral cavity.
abstract: In 2007, the International Agency for Research on Cancer presented compelling evidence that linked smokeless tobacco use to the development of human oral cancer. Although these findings imply vigorous local carcinogen metabolism, little is known about levels and distribution of phase I, II, and III (drug egress) enzymes in human oral mucosa. In this study here, we integrated clinical data, and imaging and histopathologic analyses of an oral squamous cell carcinoma that arose at the site of smokeless tobacco quid placement in a patient. Immunoblot and immunohistochemical (IHC) analyses were used to identify tumor and normal human oral mucosal smokeless tobacco-associated metabolic activation and detoxification enzymes. Human oral epithelium contains every known phase I enzyme associated with nitrosamine oxidative bioactivation with approximately 2-fold interdonor differences in protein levels. Previous studies have confirmed approximately 3.5-fold interdonor variations in intraepithelial phase II enzymes. Unlike the superficially located enzymes in nonreplicating esophageal surface epithelium, IHC studies confirmed that oral mucosal nitrosamine metabolizing enzymes reside in the basilar and suprabasilar region, which notably is the site of ongoing keratinocyte DNA replication. Clearly, variations in product composition, nitrosamine metabolism, and exposure duration will modulate clinical outcomes. The data presented here form a coherent picture consistent with the abundant experimental data that link tobacco-specific nitrosamines to human oral cancer.
authors.affiliation: Division of Oral Maxillofacial Pathology and Radiology, College of Dentistry, The Ohio State University, 2191B Postle Hall, 305 W12th Avenue, Columbus, OH 43210. mallery.1@osu.edu.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Mallery
authors.forename: Meng
authors.initials: M
authors.lastname: Tong
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Michaels
authors.forename: Amber R
authors.initials: AR
authors.lastname: Kiyani
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Hecht
mesh_terms: D001842:Bone and Bones / Q000187:drug effects; D002273:Carcinogens / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009055:Mouth / Q000187:drug effects; D009061:Mouth Mucosa / Q000187:drug effects; D009062:Mouth Neoplasms / Q000139:chemically induced* / Q000473:pathology; D009602:Nitrosamines / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D014030:Tobacco, Smokeless / Q000009:adverse effects*
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; D003577:Cytochrome P-450 Enzyme System; D010100:Oxygen