4-Aminobiphenyl-Induced Liver and Urinary Bladder DNA Adduct Formation in Cyp1a2(-/-) and Cyp1a2(+/+) Mice

Tsuneoka, Yutaka; Dalton, Timothy P.; Miller, Marian L.; Clay, Corey D.; Shertzer, Howard G.; Talaska, Glenn; Medvedovic, Mario; Nebert, Daniel W.

doi:10.1093/jnci/djg025

Cited by 61 publications

(60 citation statements)

References 49 publications

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“…In fact, our preliminary study showed that certain dietary isothiocyanates could inhibit the formation of 4-aminobiphenyl-DNA adducts in human bladder cancer cells. 4-Aminobiphenyl, a major carcinogen of human bladder cancer derived from cigarette smoking as well as occupational exposure, causes DNA damage and tumorigenic transformation in the bladder (33)(34)(35)(36), and indeed, 4-aminobiphenyl-DNA adducts were detected in a large percentage of human bladder cancer biopsies and were closely correlated to the amount of cigarettes smoked (37)(38)(39). Thus, it is possible that dietary isothiocyanates derived from cruciferous vegetables may be particularly effective in modifying smoking-related bladder carcinogenesis.…”

Section: Cancer Epidemiology Biomarkers and Prevention Cancer Epidemiomentioning

confidence: 99%

Consumption of Raw Cruciferous Vegetables is Inversely Associated with Bladder Cancer Risk

Tang¹,

Zirpoli²,

Guru

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

138

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Cruciferous vegetables contain isothiocyanates, which show potent chemopreventive activity against bladder cancer in both in vitro and in vivo studies. However, previous epidemiologic studies investigating cruciferous vegetable intake and bladder cancer risk have been inconsistent. Cooking can substantially reduce or destroy isothiocyanates, and could account for study inconsistencies. In this hospital-based case-control study involving 275 individuals with incident, primary bladder cancer and 825 individuals without cancer, we examined the usual prediagnostic intake of raw and cooked cruciferous vegetables in relation to bladder cancer risk. Odds ratios (OR) and 95% confidence intervals (CI) were estimated with unconditional logistic regression, adjusting for smoking and other bladder cancer risk factors. We observed a strong and statistically significant inverse association between bladder cancer risk and raw cruciferous vegetable intake (adjusted OR for highest versus lowest category = 0.64; 95% CI, 0.42-0.97), with a significant trend (P = 0.003); there were no significant associations for fruit, total vegetables, or total cruciferous vegetables. The associations observed for total raw crucifers were also observed for individual raw crucifers. The inverse association remained significant among current and heavy smokers with three or more servings per month of raw cruciferous vegetables (adjusted ORs, 0.46 and 0.60; 95% CI, respectively). These data suggest that cruciferous vegetables, when consumed raw, may reduce the risk of bladder cancer, an effect consistent with the role of dietary isothiocyanates as chemopreventive agents against bladder cancer. (Cancer Epidemiol Biomarkers Prev 2008; 17(4):938 -44)

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Section: Cancer Epidemiology Biomarkers and Prevention Cancer Epidemiomentioning

confidence: 99%

Consumption of Raw Cruciferous Vegetables is Inversely Associated with Bladder Cancer Risk

Tang¹,

Zirpoli²,

Guru

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

138

View full text Add to dashboard Cite

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“…For example, Cyp1a2 knockout mice do not display lower ABP-DNA adducts (Tsuneoka et al, 2003) nor protection against ABP-induced carcinogenesis (Kimura et al, 1999), despite efficient in vitro N-oxidation of this chemical to a more highly toxic hydroxylamine by Cyp1a2. Similarly, Cyp1a1 knockout mice exhibit increased rather than decreased toxicity from benzo[a]pyrene exposure (Uno et al, 2001(Uno et al, , 2004.…”

Section: Arylamine N-acetyltransferase Nat3(ϫ/ϫ) Knockout Micementioning

confidence: 99%

Effect of Arylamine AcetyltransferaseNat3Gene Knockout onN-Acetylation in the Mouse

Sugamori¹,

Brenneman²,

Wong³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Arylamine N-acetyltransferases (NAT) catalyze the biotransformation of many important arylamine drugs and procarcinogens. NAT can either detoxify or activate procarcinogens, complicating the manner in which these enzymes may participate in enhancing or preventing toxic responses to particular agents. Mice possess three NAT isoenzymes: Nat1, Nat2, and Nat3. Whereas Nat1 and Nat2 can efficiently acetylate many arylamines, few substrates appear to be appreciably metabolized by Nat3. We generated a Nat3 knockout mouse strain and used it along with our double Nat1/2(؊/؊) knockout strain to further investigate the functional role of Nat3. Nat3(؊/؊) mice showed normal viability and reproductive capacity. Nat3 expression was very low in wild-type animals and completely undetectable in Nat3(؊/؊) mice. In contrast, greatly elevated expression of Nat3 transcript was observed in Nat1/2(؊/؊) mice. We used a transcribed marker polymorphism approach to establish that the increased expression of Nat3 in Nat1/2(؊/؊) mice is a positional artifact of insertion of the phosphoglycerate kinase-neomycin resistance cassette in place of the Nat1/Nat2 gene region and upstream of the intact Nat3 gene, rather than a biological compensatory mechanism. Despite the increase in Nat3 transcript, the N-acetylation of p-aminosalicylate, sulfamethazine, 2-aminofluorene, and 4-aminobiphenyl was undetectable either in vivo or in vitro in Nat1/2(؊/؊) animals. In parallel, no difference was observed in the in vivo clearance or in vitro metabolism of any of these substrates between wild-type and Nat3(؊/؊) mice. Thus, Nat3 is unlikely to play a significant role in the N-acetylation of arylamines either in wild-type mice or in mice lacking Nat1 and Nat2 activities.

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“…DOI 10.1002/em 2 to generate C8-dG-ABP, which translates into G-T transversions in the genome that can initiate tumor growth by altering the functions of key gene products that control cell survival and proliferation. However, we [Sugamori et al, 2012] and others [Kimura et al, 1999;Tsuneoka et al, 2003] have provided evidence against the involvement of NAT1/2 and CYP1A2 in ABP bioactivation to form C8-dG-ABP, and have also observed no correlation between liver C8-dG-ABP levels and liver tumor incidence. At the same time, a consistent and markedly lower incidence of ABP-induced liver tumors was observed in female mice.…”

Section: Discussionmentioning

confidence: 53%

“…In one widely described bioactivation model based largely on in vitro studies, ABP is first N-hydroxylated by the cytochrome P450 isoform CYP1A2 to a hydroxylamine that is subsequently O-acetylated by arylamine N-acetyltransferase(s) NAT1 and/or NAT2 to form an unstable acetoxy ester [Butler et al, 1989a,b;Hammons et al, 1991;Kadlubar et al, 1991;Kerdar et al, 1993;Hlavica et al, 1997;Guengerich, 2000]. The acetoxy ester spontaneously breaks down to generate a highly reactive nitrenium ion [Novak et al, 1993;McClelland et al, 1995] that can form covalent DNA adducts, which are believed to be critical in the production of mutations that initiate or promote tumor growth Poirier et al, 1995;Otteneder and Lutz, 1999;Tsuneoka et al, 2003]. However, more recent in vivo studies using CYP1A2-deficient Cyp1a2(-/-) mice have provided evidence that is inconsistent with the above model of ABP bioactivation and tumor initiation.…”

Section: Introductionmentioning

confidence: 99%

“…Kimura et al reported that when neonatal mice were administered ABP on postnatal days 8 and 15 and assessed for liver tumor formation at 1 year of age, there was no difference in liver tumor incidence between wild-type (C57BL/6) and Cyp1a2(-/-) mice [Kimura et al, 1999]. In another study, Tsuneoka et al found higher levels of ABP-DNA adducts in adult Cyp1a2(-/-) mice than in wild-type mice following ABP exposure [Tsuneoka et al, 2003]. These studies not only call into question the role of CYP1A2 in the bioactivation of ABP to DNA-damaging metabolites in vivo, but also illustrate a striking lack of correlation between levels of ABP-DNA adducts and liver tumors, pointing to potential contributions from other cellular mechanisms in producing liver tumors following ABP exposure.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Influence of arylamine n‐acetyltransferase, sex, and age on 4‐aminobiphenyl‐induced in vivo mutant frequencies and spectra in mouse liver

Wang

Sugamori

Brenneman

et al. 2012

Environ and Mol Mutagen

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One model for cancer initiation by 4-aminobiphenyl (ABP) involves N-oxidation by cytochrome P450 CYP1A2 followed by O-conjugation by Nacetyltransferase(s) NAT1 and/or NAT2 and decomposition to a DNA-binding nitrenium ion. We recently observed that neonatal ABP exposure produced liver tumors in male but not in female mice, and that NAT deficiency reduced liver tumor incidence. However, ABP-induced liver tumor incidence did not correlate with liver levels of N-(deoxyguanosin-8-yl)-ABP adducts 24 hr after exposure. In this study, we compared in vivo ABPinduced DNA mutant frequencies and spectra between male and female wild-type and NATdeficient Muta TM Mouse using both the tumorinducing neonatal exposure protocol and a 28-day repetitive dosing adult exposure protocol. ABP produced an increase in liver DNA mutant frequencies in both neonates and adults. However, we observed no sex or strain differences in mutant frequencies in neonatally exposed mice, and higher frequencies in adult females than males. Neonatal ABP exposure of wild-type mice increased the proportion of G-T transversions in both males and females, while exposure of Nat1/2(-/-) mice produced increased G-T transversions in males and a decrease in females, even though females had higher levels of N-(deoxyguanosin-8-yl)-4-ABP adducts. There was no correlation of mutant frequencies or spectra between mice dosed as neonates or as adults. These results suggest that observed sex-and NATdependent differences in ABP-induced liver tumor incidence in mice are not due to differences in either mutation rates or mutational spectra, and that mechanisms independent of carcinogen bioactivation, covalent DNA binding and mutation may be responsible for these differences. Environ. Mol. Mutagen. 53:350-357, 2012. V V C 2012 Wiley Periodicals, Inc.

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4-Aminobiphenyl-Induced Liver and Urinary Bladder DNA Adduct Formation in Cyp1a2(-/-) and Cyp1a2(+/+) Mice

Abstract: Contrary to our expectations, CYP1A2 expression was not associated with ABP-induced hepatic oxidative stress or with ABP-DNA adduct formation. Either CYP1A2 is not the major metabolic activator of ABP or other enzymes metabolically activate ABP in mice in the absence of CYP1A2.

Cited by 61 publications

References 49 publications

Consumption of Raw Cruciferous Vegetables is Inversely Associated with Bladder Cancer Risk

Consumption of Raw Cruciferous Vegetables is Inversely Associated with Bladder Cancer Risk

Effect of Arylamine AcetyltransferaseNat3Gene Knockout onN-Acetylation in the Mouse

Influence of arylamine n‐acetyltransferase, sex, and age on 4‐aminobiphenyl‐induced in vivo mutant frequencies and spectra in mouse liver

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