Clinical and biochemical studies support smokeless tobacco's carcinogenic potential in the human oral cavity.
Clinical and biochemical studies support smokeless tobacco's carcinogenic potential in the human oral cavity.
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DOI：
10.1158/1940-6207.capr-13-0262
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Hecht SS
中科院分区：
文献类型：
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作者：
Mallery SR;Tong M;Michaels GC;Kiyani AR;Hecht SS
2007年，国际癌症研究机构提出了令人信服的证据，证明无烟烟草的使用与人类口腔癌的发展有关。虽然这些发现意味着强有力的局部致癌物代谢，很少有人知道的水平和分布的阶段I，II和药物排出酶在人类口腔粘膜。在本文介绍的研究中，我们整合了患者无烟烟草块放置部位发生的口腔鳞状细胞癌的临床数据、成像和组织病理学分析。免疫印迹和免疫组化（IHC）分析，以确定肿瘤和正常人口腔粘膜无烟烟草相关的代谢活化和解毒酶。人类口腔上皮细胞含有与亚硝胺氧化生物活化相关的每种已知I相酶，其蛋白质水平存在约2倍的供体间差异。先前的研究已证实上皮内II期酶的供体间变异约为3.5倍。与非复制食管表面上皮中位于表面的酶不同，IHC研究证实口腔粘膜亚硝胺代谢酶存在于基底和基底上区域，特别是正在进行的角质形成细胞DNA复制的部位。显然，产品成分、亚硝胺代谢和暴露持续时间的变化将调节临床结果。这里提供的数据形成了一个连贯的画面与大量的实验数据相一致，这些数据将烟草特有的亚硝胺与人类口腔癌联系起来。
In 2007, International Agency for Cancer Research presented compelling evidence that linked smokeless tobacco use to the development of human oral cancer. While these findings imply vigorous local carcinogen metabolism, little is known regarding levels and distribution of Phase I, II and drug egress enzymes in human oral mucosa. In the study presented here, we integrated clinical data, 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 employed 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 ~2 fold inter-donor differences in protein levels. Previous studies have confirmed ~3.5 fold inter-donor variations in intraepithelial Phase II enzymes. Unlike the superficially located enzymes in non-replicating esophageal surface epithelium, IHC studies confirmed 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 links tobacco-specific nitrosamines to human oral cancer.