Table 2. A list of studies on possible involvement of ROS including the hydroxyl radical in carcinogenicity Author Elliot 1986 Carcinogen Peroxisome proliferator Ye 1995 Chromium (Cr) Toyokuni 1996 Iron (Fe) Liu 1997 Chromium (Cr) Ding* 1999 Vanadium Hojo 2000 Shi 2001 Abe 2008 Chromium (Cr) Arsenic (As) Copper (Cu) Brief summary The rate of production of hydroxyl radicals was greater in fractions from the male rats treated with a peroxisome proliferator such as di(2ethylhexyl)phthalate, clofibrate or methyl clofenapate, raising a hypothesis linking such ROS to the carcinogenicity observed in rodents treated with certain peroxi some proliferators. The activation of NF κB, which may be involved in the mechanism of Cr(VI)induced carcinogenicity, was decreased by a metal chelator, DTPA or catalase, but increased by SOD. ESR measurements using DMPO confirmed that the incubation of Cr(VI) with the Jurkat cells in the presence of glutathione reductase generated hydroxyl radicals. Feinduced oxidative stress results in two possible consequences: (1) redox regulation failure that leads to lipid peroxidation and oxidative DNA and protein damage; (2) redox regulation that acti vates a variety of reducing and oxystressprotective mechanisms. Both consequences appear to play a role in Feinduced carcinogenesis. Cr(VI)glutathione complex is able to generate hydroxyl radicals via a Fentonlike reaction in the presence of molecular oxygen in aqueous medium, implying the possible involvement of Cr(IV) mediated production of hydroxyl radicals in the mechanism of Cr(VI)induced carcinogenesis. SOD and catalase but not sodium formate inhibited vanadateinduced AP1 activation, which might be a causative factor of the carcinogenicity of vanadium, in mouse epidermal JB6P1 cells, suggesting that superoxide anion and hydrogen peroxide, but not hydroxyl radicals are involved in the activation. In vivo hydroxyl radical generation in blood of mice after acute Cr(VI) intake was detected by applying ESR spintrapping technique. Superoxide anion and hydrogen peroxide were detected in keratinocytes incubated with arsenite [As(III)] concomitant with DNA damage. Since sodium formate and deferoxamine reduced the DNA damage, exposure to As(III) generates superoxide anions and hydrogen peroxide, and hydroxyl radical, derived from hydrogen peroxide, may play an important role in Asinduced skin carcinogenicity. Copper gluconate possesses carcinogenic risk toward the liver at the high dose level, and that oxida tive stress and inflammatory and proapoptotic signaling statuses may participate in its underlying mechanisms. *The study by Ding et al. was skeptical about the involvement of hydroxyl radicals in the vanadiuminduced carcinogenicity. mediated by SOD. The resultant hydrogen peroxide is then converted to the hydroxyl radical via a Fenton-like reaction. The hydroxyl radical leads to DNA damage and may activate redox- sensitive transcription factors such as NF-κB and AP-1 that have been shown to play important roles in tumor promotion.(40–44) As described above, DNA lesions can be caused by mutagenic/ carcinogenic agents. In general, a repair pathway is activated in response to such agents to preserve the integrity of the genome,(45–49) and the activation of cellular responses ranging from DNA repair and chromatin remodeling to the activation of apoptosis occurs if the damage is irreparable.(50–52) Besides the involvement of oxidative stress in metal (Cr(VI) and arsenic)-induced carcino- genicity, the cocarcinogenic and comutagenic effects of metals likely stem from their ability to interfere with DNA repair pro- cesses via DNA methylation and histone modifications,(53,54) suggesting that hydroxyl radical is one of the causative factors of metal-induced carcinogenicity (Fig. 2). De Flora commented that the carcinogenicity of Cr(VI) requires massive exposure, as is only encountered in well-defined occupa- tional settings, and is site specific, being specifically targeted to the lung and, in some cases, to the sinonasal cavity.(55) As reviewed by Smith et al.,(56) arsenic can cause liver, lung, kidney, and bladder cancer, and the population cancer risk due to arsenic in US water supplies may be comparable to that due to environmental tobacco smoke and radon in homes. In 2008, the National Toxicology Program completed a 2-year cancer bioassay for Cr(VI) in drinking water using mice. Investigators found that Cr(VI) caused tumors in the small intestines of mice and the oral mucosa of rats at 20–180 mg/l Cr(VI) in the form of sodium dichromate dihydrate.(57) Cui et al.(58) reported that chronic oral exposure of mice to inorganic arsenate(V) in drinking water for 18 months induced lung cancer. These results support the notion that long- term exposure of cells to heavy metals (Cr(VI) and arsenic) is required to cause carcinogenesis, even though the hydroxyl radical is a causative factor. There are also potential advantages to the use of the hydroxyl 12 Fig. 1. Schematic illustration of a device for the treatment of dental infectious diseases utilizing photolysis of H2O2. The photolysis of H2O2 system is incorporated into conventional ultrasound scaler. radical, being included in host immune defense utilizing radical by PMNs,(59,60) and medical applications such as for cancer treatment and antibiotics.(61,62) As an example, Kohanski reported that all three major classes of bactericidal drugs (quinolones, β-lactams, and aminoglycosides) utilize a common mechanism of killing whereby they stimulate the production of lethal amounts of hydroxyl radicals via the Fenton reaction.(62) Interestingly, Wlassoff reported a new approach to the treatment of cancer based on the innate overproduction of hydrogen peroxide in cancer cells.(63) Hydrogen peroxide serves as a prodrug in the presence of transi- doi: 10.3164/jcbn.11105 ©2012 JCBN