Shvedova A A, Kisin E R, Murray A, Kommineni C, Vallyathan V, Castranova V
Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA.
Biochemistry (Mosc). 2004 Jan;69(1):23-31. doi: 10.1023/b:biry.0000016347.35373.39.
Organic peroxides used in the chemical and pharmaceutical industries have a reputation for being potent skin tumor promoters and inducers of epidermal hyperplasia. Their ability to trigger free radical generation is critical for their carcinogenic properties. Short-term in vivo exposure of mouse skin to cumene hydroperoxide (Cum-OOH) causes severe oxidative stress and formation of spin-trapped radical adducts. The present study was designed to determine the effectiveness of Cum-OOH compared to 12-O-tetradecanoylphorbol-13-acetate (TPA) in the induction of tumor promotion in the mouse skin, to identify the involvement of cyclooxygenase-2 (COX-2) in oxidative metabolism of Cum-OOH in keratinocytes, and to evaluate morphological changes and outcomes of oxidative stress in skin of SENCAR mice throughout a two-stage carcinogenesis protocol. Dimethyl-benz[a]anthracene (DMBA)-initiated mice were treated with Cum-OOH (32.8 micro mol) or TPA (8.5 nmol) twice weekly for 20 weeks to promote papilloma formation. Skin carcinoma formed only in DMBA/Cum-OOH-exposed mice. Higher levels of oxidative stress and inflammation (as indicated by the accumulation of peroxidative products, antioxidant depletion, and edema formation) were evident in the DMBA/Cum-OOH group compared to DMBA/TPA treated mice. Exposure of keratinocytes (HaCaT) to Cum-OOH for 18 h resulted in expression of COX-2 and increased levels of PGE(2). Inhibitors of COX-2 efficiently suppressed oxidative stress and enzyme expression in the cells treated with Cum-OOH. These results suggest that COX-2-dependent oxidative metabolism is at least partially involved in Cum-OOH-induced inflammatory responses and thus tumor promotion.
化学和制药行业中使用的有机过氧化物素有强效皮肤肿瘤促进剂和表皮增生诱导剂之称。它们引发自由基生成的能力对其致癌特性至关重要。小鼠皮肤短期体内暴露于氢过氧化异丙苯（Cum-OOH）会导致严重的氧化应激和自旋捕获自由基加合物的形成。本研究旨在确定Cum-OOH与12-O-十四酰佛波醇-13-乙酸酯（TPA）相比在诱导小鼠皮肤肿瘤促进方面的有效性，确定环氧合酶-2（COX-2）在角质形成细胞中Cum-OOH氧化代谢中的作用，并在整个两阶段致癌方案中评估SENCAR小鼠皮肤氧化应激的形态学变化和结果。用二甲基苯并[a]蒽（DMBA）启动的小鼠每周两次接受Cum-OOH（32.8微摩尔）或TPA（8.5纳摩尔）处理，持续20周以促进乳头瘤形成。皮肤癌仅在暴露于DMBA/Cum-OOH的小鼠中形成。与接受DMBA/TPA处理的小鼠相比，DMBA/Cum-OOH组中氧化应激和炎症水平更高（以过氧化产物积累、抗氧化剂消耗和水肿形成表示）。角质形成细胞（HaCaT）暴露于Cum-OOH 18小时导致COX-2表达和PGE(2)水平升高。COX-2抑制剂有效抑制了Cum-OOH处理细胞中的氧化应激和酶表达。这些结果表明，COX-2依赖性氧化代谢至少部分参与了Cum-OOH诱导的炎症反应，从而参与了肿瘤促进过程。
