Nonenzymatic Reduction of Nitro Derivative of a Heterocyclic Amine IQ by NADH and Cu(II) Leads to Oxidative DNA Damage

Murata, Mariko; Kobayashi, Mikiko; Kawanishi, Shosuke

doi:10.1021/bi982906b

Cited by 23 publications

(8 citation statements)

References 41 publications

(47 reference statements)

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“…In view of the molecular mechanisms, two types of direct DNA adducts, the major N ‐(deoxyguanosin‐8‐yl)‐IQ and the minor 5‐(deoxyguanosin‐ N 2 ‐yl)‐IQ, are thought to be responsible for IQ‐mutagenesis [19,36]. It has also been suggested that oxidative DNA damage with 8‐OHdG formation as a result of nonenzymatic reduction of nitro‐IQ may play a role in carcinogenesis [37]. Although, we could not determine which type of DNA lesion was responsible for the IQ‐induced hepatocarcinogenesis, recent work with a panel of biomarkers for detecting oxidative stress, DNA damage, and expression of DNA repair enzymes in IQ‐treated BigBlue rats pointed to specific DNA adducts rather than oxidative DNA damage as responsible for IQ initiation of hepatocarcinogenesis [38].…”

Section: Discussionmentioning

confidence: 99%

In vivo mutational analysis of liver DNA in gpt delta transgenic rats treated with the hepatocarcinogens N‐nitrosopyrrolidine, 2‐amino‐3‐methylimidazo[4,5‐f]quinoline, and di(2‐ethylhexyl)phthalate

Kanki

Nishikawa

Masumura

et al. 2004

Molecular Carcinogenesis

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In order to cast light on carcinogen-specific molecular mechanisms underlying experimental hepatocarcinogenesis in rats, in vivo mutagenicity and mutation spectra of known genotoxic rat hepatocarcinogens N-nitrosopyrrolidine (NPYR), and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), as well as the nongenotoxic hepatocarcinogen di(2-ethylhexyl)phthalate (DEHP) and the noncarcinogen acetaminophen (AAP), were investigated in guanine phosphoribosyltransferase (gpt) delta transgenic rats, a recently developed animal model for genotoxicity analysis. After 13-wk treatment, glutathione S-transferase placental form (GST-P)-positive liver cell foci were significantly increased in NPYR-treated and IQ-treated rats. In the DEHP-treated rats, marked hepatomegaly with centrilobular hypertrophy of hepatocytes occurred, although GST-P staining was consistently negative. Positive mutagenicity was detected in IQ- and NPYR-treated rats. Mutant frequencies (MFs) in the liver DNA were 188.0 x 10(-6) and 56.5 x 10(-6), approximately 35-fold and 10-fold higher, respectively, than that of nontreatment control rats (5.5 x 10(-6)). There were no increases in MFs in the DEHP- or AAP-treated rats as compared to the nontreatment control value. IQ induced mainly base substitutions leading to G:C to T:A transversions (56.9%) and deletions of G:C base pairs. In contrast, NPYR primarily caused specific A:T to G:C transitions (49.3%), which are very rare in the other groups. These data provided support for the conclusion that IQ and NPYR hepatocarcinogenesis depends on genotoxic processes and specific DNA adduct formation while DEHP exerts its influence via a nongenotoxic promotional pathway. Our data also indicate that analysis of specific in vivo mutational responses with transgenic animal models can provide crucial information for understanding the molecular mechanisms underlying chemical carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

In vivo mutational analysis of liver DNA in gpt delta transgenic rats treated with the hepatocarcinogens N‐nitrosopyrrolidine, 2‐amino‐3‐methylimidazo[4,5‐f]quinoline, and di(2‐ethylhexyl)phthalate

Kanki

Nishikawa

Masumura

et al. 2004

Molecular Carcinogenesis

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“…26,27 This nitro-IQ was reported to cause DNA damage, including the formation of 8-hydroxydeoxyguanosine , in the presence of NADH and Cu 21 in vitro, indicating that oxidative DNA damage may be involved in the carcinogenicity of nitro-IQ. 28 As HCAs and nitrite are present in food, particularly in cooked red meats 29 and vegetables, 10 it is important to investigate combination effects of IQ and NaNO 2 to access human risk.…”

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confidence: 99%

Enhancing effects of simultaneous treatment with sodium nitrite on 2‐amino‐3‐methylimidazo[4,5‐f]quinoline‐induced rat liver, colon and Zymbal's gland carcinogenesis after initiation with diethylnitrosamine and 1,2‐dimethylhydrazine

Kitamura

Umemura

Okazaki

et al. 2006

Intl Journal of Cancer

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Combined effects of sodium nitrite (NaNO 2 ) and 2-amino-3-methylimidazo [4,5-f]quinoline (IQ) on liver, colon and Zymbal's gland carcinogenesis were assessed using a rat two-stage carcinogenesis model, with a focus on involvement of oxidative stress. Male 6-week-old F344 rats were given a single intraperitoneal injection of 200 mg/kg of diethylnitrosamine and 4 subcutaneous injections of 40 mg/kg of 1,2-dimethylhydrazine for initiation. Then, they were administered 0 or 300 ppm IQ in the diet or 0, 0.1 or 0.2% NaNO 2 in their drinking water for 27 weeks. The treatment with NaNO 2 1 IQ significantly enhanced colon and Zymbal's gland carcinogenesis and tended to enhance hepatocarcinogenesis. The incidence of lung tumors in the IQ-treated groups was significantly increased as compared with the initiation alone group. In a second experiment, male rats were given IQ or NaNO 2 under the same conditions as before for 1 week, and at sacrifice, their liver and colon tissue or mucosa were collected for analysis of 8-hydroxydeoxyguanosine (8-OHdG), thiobarbituric acid reactive substances (TBARS), acrolein-modified protein and the bromodeoxyuridine-labeling index (BrdU-LI) (in the colon). In the colon, 8-OHdG, acrolein-modified protein levels and BrdU-LI were significantly increased by the combined treatment. These results indicate that the treatment with NaNO 2 enhances IQ-induced colon and Zymbal's gland carcinogenesis in rats and that oxidative DNA damage and lipid peroxidation may partly be involved, especially in the colon. In addition, this experiment showed that IQ can act as a potent lung carcinogen in rats. ' 2005 Wiley-Liss, Inc.Key words: sodium nitrite; 2-amino-3-methylimidazo[4,5-f]quinoline; liver carcinogenesis; colon carcinogenesis; oxidative stress 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ), one of the mutagenic and carcinogenic heterocyclic amines (HCA), has been detected in cooked meat and fish 1 and also in cigarette smoke condensate.2 Long-term experiments using rodents have demonstrated that IQ is carcinogenic to the liver, colon, small intestine, Zymbal's gland, clitoral gland and skin in F344 rats 3 and to the liver, forestomach and lung in CDF 1 mice. 4 Metabolically activated IQ forms DNA adducts in liver of rats, mice and monkeys in vivo 1 and in bacteria in vitro.5 In F344 rats, IQ-specific DNA adducts have been detected in the lungs, kidneys, stomach, large intestine, white blood cells and small intestine.6 It was recently suggested that oxidative stress may also participate in HCA carcinogenesis, based on the finding that HCA-induction of preneoplastic or neoplastic lesions was significantly inhibited when antioxidants were given simultaneously 7,8 and that superoxide anion radicals were generated during NADPH/cytochrome P-450 reductase-mediated metabolic activation of HCAs in vitro using a spin-trapping method. 9Sodium nitrite (NaNO 2 ) is used as a color fixative and preservative for meats and fish, and it is also present in vegetables. 10Although it is generally accepted that NaNO 2 is n...

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“…The concentration of NAD(P)H in certain tissue has been estimated to be as high as 100 -200 M (23). The biological importance of NADH and NADPH as nuclear reductants (24) has been demonstrated before (25,26). This non-enzymatic reduction of 1-NOP by NADH, causing oxidative DNA damage, is yet another example of its relevance.…”

Section: Discussionmentioning

confidence: 98%

Oxidative DNA Damage by a Metabolite of Carcinogenic 1-Nitropyrene

Ohnishi

Murata

Fukuhara

et al. 2001

Biochemical and Biophysical Research Communications

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Nonenzymatic Reduction of Nitro Derivative of a Heterocyclic Amine IQ by NADH and Cu(II) Leads to Oxidative DNA Damage

Cited by 23 publications

References 41 publications

In vivo mutational analysis of liver DNA in gpt delta transgenic rats treated with the hepatocarcinogens N‐nitrosopyrrolidine, 2‐amino‐3‐methylimidazo[4,5‐f]quinoline, and di(2‐ethylhexyl)phthalate

In vivo mutational analysis of liver DNA in gpt delta transgenic rats treated with the hepatocarcinogens N‐nitrosopyrrolidine, 2‐amino‐3‐methylimidazo[4,5‐f]quinoline, and di(2‐ethylhexyl)phthalate

Enhancing effects of simultaneous treatment with sodium nitrite on 2‐amino‐3‐methylimidazo[4,5‐f]quinoline‐induced rat liver, colon and Zymbal's gland carcinogenesis after initiation with diethylnitrosamine and 1,2‐dimethylhydrazine

Oxidative DNA Damage by a Metabolite of Carcinogenic 1-Nitropyrene

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