Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (7)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Nomoto, M.
Right arrow Articles by Kasai, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nomoto, M.
Right arrow Articles by Kasai, H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Carcinogenesis, Vol. 20, No. 5, 837-841, May 1999
© 1999 Oxford University Press

Analysis of 8-hydroxyguanine in rat kidney genomic DNA after administration of a renal carcinogen, ferric nitrilotriacetate

Minoru Nomoto3, Raizo Yamaguchi2, Masaru Kawamura1, Kimitoshi Kohno and Hiroshi Kasai2

Department of Molecular Biology and
1 Department of Biology, School of Medicine and
2 Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health Japan, Kitakyushu 807, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
The frequency of oxidative base damage, such as 8-hydroxyguanine (8-OH-Gua), was determined at the nucleotide level of resolution using the ligation-mediated PCR technique. Administration of a renal carcinogen, ferric nitrilotriacetate (Fe-NTA), is known to induce oxidative stress and subsequent formation of 8-OH-Gua in the rat kidney. Whole genomic DNA was isolated from the rat kidney after or without Fe-NTA treatment and then cleaved with hot piperidine. In order to assess the frequency of 8-OH-Gua formation, we chose three genes, the tumor suppressor gene p53, the heat shock protein 70 (HSP70-1) gene and the Na,K-ATPase {alpha}1 subunit gene. No alteration in the cleavage profile was observed in the p53 and HSP70 genes after Fe-NTA treatment. In the case of the p53 gene, a low incidence of point mutations has been observed in this carcinogenesis system. On the other hand, time-dependent alterations, corresponding to the time course of overall 8-OH-Gua formation and repair, were detected in the promoter region of the Na,K-ATPase {alpha}1 subunit gene. GpG and GpGpG in specific regions seem to be hotspots for the formation of 8-OH-Gua. These results were confirmed by formamidopyrimidine-DNA glycosylase-dependent DNA cleavage patterns. Thus, oxidative base damage, such as 8-OH-Gua, was not distributed uniformly along the whole genome, but seemed to be restricted to particular genes and regions.

Abbreviations: DMS, dimethylsulfate; Fe-NTA, ferric nitriloacetate; Fpg, formamidopyrimidine-DNA glycosylase; LM-PCR, ligation-mediated polymerase chain reaction; 8-OH-Gua, 8-hydroxyguanine; ROS, reactive oxygen species.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Reactive oxygen species (ROS) induce several kinds of DNA damage, for example single-strand breaks, double-strand breaks, base modifications, including apurinic and apyrimidic sites, and DNA–protein crosslinking (1–3). Such damage is an important intermediate in the pathogenesis of cancer and in aging, because many ROS-induced base modifications are promutagenic (4–13). 8-Hydroxyguanine (8-OH-Gua) is a major form of oxidative DNA damage (14,15), which induces mainly GC->TA transversions in Escherichia coli and mammalian cells (16). The 8-OH-Gua level in cellular DNA can be measured with high sensitivity (17,18). However, the relationship between the induced DNA damage and mutation spectra has not been elucidated, because a suitable method for detecting damaged nucleotides in DNA in vivo has yet to be established.

Recently, an application of ligation-mediated PCR (LM-PCR) brought about a breakthrough in the detection of damaged nucleotides at the nucleotide level of resolution (19). LM-PCR was initially developed for genomic sequencing, including the detection of CpG methylation sites, and also for in vivo footprinting (20–22). Based on our experience with LM-PCR (23,24), we tried to elucidate the distribution of 8-OH-Gua within the genome; whether 8-OH-Gua was scattered in the whole genome with almost equal frequency or had a restricted distribution in particular genes or regions. The ultimate goal of this project was to determine the target gene(s) of this chemical carcinogenesis system.

In the present study, we observed a time-dependent alteration of hot piperidine-cleaved sites, corresponding to 8-OH-Gua formation and repair, in the upstream region of the Na,K-ATPase {alpha}1 subunit gene, whereas no time-dependent cleavage was observed in the p53 or HSP70-1 genes. Moreover, a similar cleavage pattern in the promoter region of the Na,K-ATPase {alpha}1 gene was observed in formamidopyrimidine-DNA glycosylase (Fpg)-digested genomic DNA. These results suggest that oxidative damage, such as 8-OH-Gua, preferentially occurred in restricted genes or regions.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Animals
Six-week-old male Wistar rats were purchased from Seiwa Experimental Animal (Fukuoka, Japan). They were provided with commercial rat chow (Clea, Tokyo, Japan) and tap water ad libitum and were used after 4 days of acclimatization.

Chemicals and Fpg
Fe(NO3)3, Na2NTA and the DNA Extractor WB Kit were purchased from Wako Biochemicals (Osaka, Japan). Piperidine and dimethylsulfate (DMS) were from Nacalai Tesque (Kyoto, Japan). The ferric nitriloacetate (Fe-NTA) solution was prepared immediately before use by the method of Awai et al. (25), with a slight modification. Briefly, Fe(NO3)3 and Na2NTA were each dissolved in Milli-Q water and then mixed at a molar ratio of 1:4. The pH was adjusted to 7.4 with NaHCO3. Fpg was purchased from Trevigen (catalog no. 4040-100-01). Fpg digestion of genomic DNA was performed according to the manufacturer's instructions.

Protocol of Fe-NTA treatment
A total of 30 animals were divided into either the Fe-NTA or control groups. In the Fe-NTA group, they were killed 1, 6, 24, 72 and 120 h after injection of Fe-NTA (15 mg Fe/kg body wt i.p.). In the control group, they were killed without any treatment. Each subgroup contained five animals. The animals were killed under ether anesthesia. The kidneys were immediately removed and then used for the experiments. A part of the organ was frozen and kept at –80°C.

Ligation-mediated PCR (LM-PCR)
DNA was extracted from the rat kidneys (100–200 mg) with the DNA Extractor WB Kit according to the method of Nakae et al. (26). The extracted DNA was cleaved with 1 M piperidine at 90°C for 30 min (27,28). As a control guanine ladder, an aliquot of genomic DNA from control animals was reacted with DMS and cleaved with piperidine as described above. LM-PCR was performed as described previously (23,24). The nucleotide sequences of individual primers were as follows. For p53 gene exon 6: primer 1, 5'-GCTGGGGAGGACCGG-3'; primer 2, 5'-CCAGCCCAACCTGGCACACAGC-3'; primer 3, 5'-CAGCCCAACCTGGCACACAGCTTCCTACCTGG-3' (29,30). For HSP70 gene: primer 1, 5'-GCGAGTGGAACCAGAAACTG-3'; primer 2, 5'-CTGGTGTCCTGCGCGCCG; primer 3, 5'-GGTGTCCTGCGCGCCGCCCTGC-3' (24). For the upper strand of Na,K-ATPase {alpha}1 subunit gene: primer 1, 5'-CACGTGTCCGCCTCCTC-3'; primer 2, 5'-CCTCCCGCCGAGGCTCC-3'; primer 3, 5'-CTCCCGCCGAGGCTCCGCGCC-3'. For the lower strand of Na,K-ATPase {alpha}1 subunit gene: primer 1, 5'-CTAGAGACCGGGGCACTC-3'; primer 2, 5'-GGCGCCCTCCTGCCGG-3'; primer 3, 5'-GCGCCCTCCTGCCGGGAGCCC-3' (23). Primers 1 and 2 were used for the first-strand synthesis and PCR amplification, respectively. Primers 3 were labeled at the 5'-end with [{gamma}-32P]ATP and used for final detection of the ladder.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Main hotspot codons of p53 gene mutation have been observed in exon 5 (codons 154, 157, 175 and 179), exon 7 (codons 245, 248 and 249) and exon 8 (codons 267, 273, 282 and 306) in human (31,32). In the case of the rat genome, exon 6 of the p53 gene corresponds to human p53 exons 6 and 7 with a fused exon organization (29). No marked cleavage site with a time-dependent fluctuation in signal intensity was observed in exons 5, 6 or 7. The results for exon 6 are shown in Figure 1AGo, as a representative analysis. Some background signals, not corresponding to guanine residues, were observed. Although a few signals in guanine positions were detected, for example the second letter of codon 249, a time-dependent fluctuation could not be observed. A similar situation was observed for the HSP70-1 gene, as shown in Figure 1BGo.



View larger version (73K):
[in this window]
[in a new window]
  		Fig. 1. Piperidine cleavage profiles of the p53 and HSP70-1 genes. The distribution of cleavage sites on genomic DNA from kidneys at the indicated times after Fe-NTA treatment or control kidney without treatment were analyzed by LM-PCR. Genomic DNA from kidney of control animals was also reacted with DMS, then cleaved with piperidine. The resulting LM-PCR product was used as a guanine (G) ladder. Cleavage profiles of p53 gene exon 6 (A) and the promoter region of the HSP70-1 gene (B) on the non-transcribed strand are shown.

 
On the other hand, time-dependent cleaved signals at guanine residues were detected at –143, –129, –93, –13, –4, –3 and +13 in the upper strand (non-transcribed strand) of the Na,K-ATPase {alpha}1 subunit gene, as shown in Figure 2AGo. Such cleaved guanine signals were also observed at –95 and –138 in the lower strand (transcribed strand) of the gene (Figure 2BGo). These cleavage sites were found within particular GpG and GpGpG sequences or their penultimate nucleotides. The location of GpG and GpGpG sequences are shown to the left of each figure and potential target sites are indicated by capital letters (Figure 2A and BGo). Interestingly, some time-dependent cleavage signals, not corresponding to guanine residues, could be seen at –95 (cytosine, C) and –79 (C) in the upper strand and at +13 (C), –13 (C) and –94 (C) in the lower strand. These additional cleaved sites located at bases (+13, –13 and –95) opposite guanine residues were detected as time-dependent cleaved signals in the complementary strand. Quantitative results of the cleavage signals in question are summarized in Table IGo. These cleavage profiles were reproducibly obtained even in different batches of genomic DNA preparations (data not shown). To confirm that these cleavage signals are indeed derived from 8-OH-Gua, we digested the Fe-NTA-treated genomic DNA with Fpg. A similar cleavage pattern was obtained, as shown in Figure 3Go, and the results of quantitative analyses are listed in Table IIGo. These results strongly suggest that 8-OH-Gua formation was highly restricted in the genome. Although we detected some cleavage signals in the promoter region of the Na,K-ATPase {alpha}1 gene (Figures 2 and 4GoGo), it is not easy to perform a similar analysis on the coding region of the Na,K-ATPase {alpha}1 gene because of other {alpha} subunit genes which encode highly homologous amino acid sequences. Based on the nucleotide sequences of particular regions encoding clustered amino acid substitutions between {alpha} subunits, we analyzed the piperidine cleavage sites in the coding region of the Na,K-ATPase {alpha}1 subunit gene (the transcribed strand of exon 12 and the non-transcribed strand of exon 10). However, significant time-dependent signals were not detected (data not shown).



View larger version (77K):
[in this window]
[in a new window]
  		Fig. 2. Piperidine cleavage profiles of the promoter region of the Na,K-ATPase {alpha}1 gene. Cleavage profiles for the non-transcribed strand (A) and transcribed strand (B) are shown. Cleavage sites with time-dependent fluctuations in signal intensity are marked at the right side of each panel with nucleotide numbers. Positions of GpG and GpGpG sequences are indicated at the left side of each panel, in capital (potential reactive site) or lower case (inert site) letters.

 

View this table:
[in this window]
[in a new window]
  		Table I. Quantitative results of major cleavage signals in Figure 2A and BGo
 


View larger version (55K):
[in this window]
[in a new window]
  		Fig. 3. Comparison of cleavage profiles on piperidine treatment and Fpg digestion. The distribution of cleavage sites of genomic DNA after digestion by Fpg or without digestion (No Enz.) were compared with that of piperidine treatment (Pip.). Cleavage profiles for the non-transcribed strand of the Na,K-ATPase {alpha}1 gene promoter region are shown.

 

View this table:
[in this window]
[in a new window]
  		Table II. Quantitative results of major cleavage signals in Figure 3Go
 


View larger version (15K):
[in this window]
[in a new window]
  		Fig. 4. Comparison of distribution of piperidine cleavage sites and DMS-hypersensitive sites. Piperidine cleavage sites on the core promoter region of the Na,K-ATPase {alpha}1 gene are summarized in the upper part of the figure. The closed and open arrows denote the cleavage site at guanine and at other nucleotide residues, respectively. Sites hypersensitive to DMS are shown with a closed arrow in the lower part of the figure. The distribution of hypersensitive sites is taken from our previous report (23).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In order to analyze 8-OH-Gua formation in vivo, we used hot piperidine-treated genomic DNA, since 8-OH-Gua is known to be cleaved upon piperidine treatment (28). The genomic DNA fragments were subjected to LM-PCR. We chose three genes for the analysis, the tumor suppressor gene p53, the HSP70-1 gene and the Na,K-ATPase {alpha}1 subunit gene. The p53 gene is a negative control for 8-OH-Gua formation, because mutation of the p53 gene is not found in this Fe-NTA chemical carcinogenesis system (33). The HSP70-1 gene is not induced under non-stressed conditions (34). The Na,K-ATPase {alpha}1 subunit gene is active in kidney, although its expression in other tissues is relatively low (35,36). As shown in Figure 1Go, cleavage signals were observed in positions not corresponding to guanine bases and/or they did not show any time-dependent alteration in signal intensity. Because these signals were not observed in piperidine-untreated genomic DNA samples (data not shown), with the exception of the Na,K-ATPase {alpha}1 gene promoter (Figure 3Go), they are probably derived from base modifications which could be cleaved by piperidine. Indeed, such additional cleavage signals were significantly reduced in intensity in Fpg-digested samples (Figure 3Go).

Conspicuous signals with time-dependent fluctuations in signal intensity were observed at –93 and –95 in the non-transcribed strand and –95 in the transcribed strand of the Na,K-ATPase {alpha}1 subunit gene. The signal intensity of these positions was relatively high even in Fe-NTA-untreated `control' samples (Figure 2Go). Since faint signals at –93 and –95 were observed even in undigested DNA samples (Figure 3Go), these sites might be highly reactive with very poor repair efficiency. Thus, a portion of DNA seems to maintain a nicked state (Tables I and IIGoGo). Although the overall 8-OH-Gua level within the whole genome increased several-fold at 1 h after Fe-NTA treatment, slightly decreased at 6 h and then returned to the control level at 24 h after Fe-NTA treatment (37), the time points showing maximum intensity in our analysis differed slightly among cleaved positions (Figures 2 and 3GoGo and Tables I and IIGoGo). These observations suggest that for each nucleotide in question, the equilibrium constant for formation and repair of modification differed. As described above, reduced levels of background signals were observed in Fpg-digested DNA samples (Figure 3Go) and maximum intensity values with respect to controls in Fpg digests were higher than the peak values in piperidine-treated DNA samples (Table IIGo versus Table IGo). This suggests that the piperidine cleavage sites in question could be targets not only for hydroxylation but also for some other modifications being reactive to piperidine. Although we observed some cleavage signals at cytosine residues, including –94 in the transcribed strand and –95 in the non-transcribed strand, we do not know the chemical entity of the modification at present.

As summarized in Figure 4Go, the distribution of 8-OH-Gua sites is highly homologous to that of DMS-hypersensitive sites reported previously (23). This observation suggests that the region could be accessible to both hydroxy radical and DMS attacks. The accessiblity might be derived from an altered or open structure in chromatin. Our observations demonstrate that preferential adduct formation in the non-transcribed strand by transcription coupled repair (19,38,39) is not the case in oxidative DNA damage in the promoter region of the Na,K-ATPase {alpha}1 gene.


   Acknowledgments
 
This work was supported by grants in Aid from the Ministry of Education, Science and Culture of Japan.


   Notes
 
3 To whom correspondence should be addressed Email: m-nomoto{at}mail.med.uoeh-u.ac.jp Back


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Dizdaroglu,M. (1991) Chemical determination of free radical-induced damage to DNA. Free Radic. Biol. Med., 10, 225–242.[ISI][Medline]
  2. Halliwell,B. and Aruoma,O.I. (1991) DNA damage by oxygen-derived species. Its mechanism and measurement in mammalian systems. FEBS Lett., 281, 9–19.[ISI][Medline]
  3. Dizdaroglu,M. (1992) Oxidative damage to DNA in mammalian chromatin. Mutat. Res., 275, 331–342.[ISI][Medline]
  4. Loeb,L.A., James,E.A., Waltersdorph,A.M. and Klebanoff,S.J. (1988) Mutagenesis by the autooxidation of iron with isolated DNA. Proc. Natl Acad. Sci. USA, 85, 3918–3922.[Abstract/Free Full Text]
  5. Basu,A.K., Loechler,E.L., Leadon,S.A. and Essigmann,J.M. (1989) Genetic effects of thymine glycol: site-specific mutagenesis and molecular modeling studies. Proc. Natl Acad. Sci. USA, 86, 7677–7681.[Abstract/Free Full Text]
  6. Wood,M.L., Dizdaroglu,M., Gajewski,E. and Essigmann,J.M. (1990) Mechanistic studies of ionizing radiation and oxidative mutagenesis: genetic effects of a single 8-hydroxyguanine (7-hydro-8-oxoguanine) residue inserted at a unique site in a viral genome. Biochemistry, 29, 7024–7032.[Medline]
  7. McBride,T.J., Preston,B.D. and Loeb,L.A. (1991) Mutagenic spectrum resulting from DNA damage by oxygen radicals. Biochemistry, 30, 207–213.[Medline]
  8. Akman,S.A., Forrest,G.P., Doroshow,J.H. and Dizdaroglu,M. (1991) Mutation of potassium permanganate- and hydrogen peroxide-treated plasmid pZ189 replicating in CV-1 monkey kidney cells. Mutat. Res., 261, 123–130.[ISI][Medline]
  9. Moriya,M., Ou,C., Bodepudi,V., Johnson,F., Takeshita,M. and Grollman,A.P. (1991) Site-specific mutagenesis using a gapped duplex vector: a study of translesion synthesis past 8-oxodeoxyguanosine in E.coli. Mutat. Res., 254, 281–288.[ISI][Medline]
  10. Tkeshelashvili,L.K., McBride,T., Spence,K. and Loeb,L.A. (1991) Mutation spectrum of copper-induced DNA damage. J. Biol. Chem., 266, 6401–6406.[Abstract/Free Full Text]
  11. Weitzman,S.A. and Gordon,L.I. (1990) Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis. Blood, 76, 655–663.[Abstract/Free Full Text]
  12. Feig,D.I., Sowers,L.C. and Loeb,L.A. (1994) Reverse chemical mutagenesis: identification of the mutagenic lesions resulting from reactive oxygen species-mediated damage to DNA. Proc. Natl Acad. Sci. USA, 91, 6609–6613.[Abstract/Free Full Text]
  13. Maccabee,M., Evans,J.S., Glackin,M.P., Hahahet,Z. and Wallace,S.S. (1994) Pyrimidine ring fragmentation products. Effects of lesion structure and sequence context on mutagenesis. J. Mol. Biol., 236, 514–530.[ISI][Medline]
  14. Kasai,H. and Nishimura,S. (1993) Formation of 8-hydroxyguanine by oxidative DNA damage, its repair and its mutagenic effects. In de Obe,G. (ed.) Advances in Mutagenesis Research. Springer-Verlag, Berlin, Germany, Vol. 4, pp. 31–45.
  15. Umemura,T., Sai,K., Takagi,A., Hasegawa,R. and Kurokawa,Y. (1990) Formation of 8-hydroxydeoxyguaosine (8-OH-dG) in rat kidney DNA after intraperitoneal administration of ferric nitrilotriacetate (Fe-NTA). Carcinogenesis, 11, 345–347.[Abstract/Free Full Text]
  16. Cheng,K.C., Cahill,D.S., Kasai,H., Nishimura,S. and Loeb,L.A. (1992) 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G->T and A->C substitutions. J. Biol. Chem., 267, 166–172.[Abstract/Free Full Text]
  17. Floyd,R.A., Watson,J.J., Wong,P.K., Altmiller,D.H. and Rickard,R.C. (1986) Hydroxy free radical adduct of deoxyguanosine: sensitive detection and mechanisms of formation. Free Radic. Res. Commun., 1, 163–172.[Medline]
  18. Kasai,H. (1997) Analysis of a form of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat. Res., 387, 147–163.[ISI][Medline]
  19. Denissenko,M.F., Pao,A., Tang,M.-S., Pfeifer,G.P. (1996) Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53. Science, 274, 430–432.[Abstract/Free Full Text]
  20. Mueller,P.R. and Wold,B. (1989) In vivo footprinting of a muscle specific enhancer by ligation mediated PCR. Science, 246, 780–786.[Abstract/Free Full Text]
  21. Pfeifer,G.P., Steigerwald,S.D., Mueller,P.R., Wold,B. and Riggs,A.D. (1989) Genomic sequencing and methylation analysis by ligation mediated PCR. Science, 246, 810–813.[Abstract/Free Full Text]
  22. Mueller,P.R. and Wold,B. (1991) Ligation-mediated PCR for genomic sequencing and footprinting. In Ausubel,F.M., Brent,R., Kingston,R.E. et al. (eds) Current Protocols in Molecular Biology. Greene and Wiley, New York, NY, Suppl. 14, pp. 15.5.1–15.5.16,
  23. Nomoto,M., Gonzalez,F.J., Mita,T., Inoue,N. and Kawamura,M. (1995) Analysis of cis-acting regions upstream of the rat Na+/K+-ATPase {alpha}1 subunit gene by in vivo footprinting. Biochim. Biophys. Acta, 1264, 35–39.[Medline]
  24. Konishi,T., Nomoto,M., Shimizu,K., Abe,T., Itoh,H., Friedrich,H., Guenther,E. and Higashi,K. (1995) Dominant role of the second heat shock element in expression of the HSP70-1 gene in rat liver after whole body hyperthermia. J. Biochem., 118, 1021–1029.[Abstract/Free Full Text]
  25. Awai,M., Narasaki,M., Yamanoi,Y. and Seno,S. (1979) Induction of diabetes in animals by parenteral administration of ferric nitrilotriacetate. A model of experimental hemochromatosis. Am. J. Pathol., 95, 663–674.[Abstract]
  26. Nakae,D., Mizumoto,Y., Kobayashi,E., Noguchi,O. and Konishi,Y. (1995) Improved genomic/nuclear DNA extraction for 8-hydroxydeoxyguanosine analysis of small amounts of rat liver tissue. Cancer Lett., 97, 233–239.[ISI][Medline]
  27. Maxam,A.M. and Gilbert,W. (1977) A new method for sequencing DNA. Proc. Natl Acad. Sci. USA, 74, 560–564.[Abstract/Free Full Text]
  28. Chung,M.-H., Kiyosawa,H., Ohtsuka,E., Nishimura,S. and Kasai,H. (1992) DNA strand cleavage at 8-hydroxyguanine residues by hot piperidine treatment. Biochem. Biophys. Res. Commun., 188, 1–7.[ISI][Medline]
  29. Hulla,J.E. and Schneider,R.P.S. (1993) Structure of the rat p53 tumor suppressor gene. Nucleic Acids Res., 21, 713–717.[Abstract/Free Full Text]
  30. Nickell-Brady,C., Hahn,F.F., Finch,G.L. and Belinsky,S.A. (1994) Analysis of K-ras, p53 and c-raf-1 mutations in beryllium-induced rat lung tumors. Carcinogenesis, 15, 257–262.[Abstract/Free Full Text]
  31. Hollstein,M., Sidransky,D., Vogelstein,B. and Harris,C.C. (1991) p53 mutations in human cancers. Science, 253, 49–53.[Abstract/Free Full Text]
  32. Greenblatt,M.S., Bennett,W.P., Hollstein,M. and Harris,C.C. (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res., 54, 4855–4878.[Free Full Text]
  33. Nishiyama,Y., Suwa,H., Okamoto,K., Fukumoto,M., Hiai,H. and Toyokuni,S. (1995) Low incidence of point mutations in H-, K- and N-ras oncogenes and p53 tumor suppressor gene in renal cell carcinoma and peritonel mesothelioma of wistar rats induced by ferric nitrilotriacetate. Jpn. J. Cancer Res., 86, 1150–1158.[ISI][Medline]
  34. Guenther,E. and Walter,L. (1994) Genetic aspects of the hsp70 multigene family in vertebrates. Experientia, 50, 987–1001.[ISI][Medline]
  35. Young,R.M. and Lingrel,J.B. (1987) Tissue distribution of mRNAs encoding the {alpha} isoforms and ß subunit of rat Na+,K+-ATPase. Biochem. Biophys. Res. Commun., 145, 52–58.[ISI][Medline]
  36. Yagawa,Y., Kawakami,K. and Nagano,K. (1990) Cloning and analysis of the 5'-flanking region of rat Na+/K+-ATPase {alpha}1 subunit gene. Biochim. Biophys. Acta, 1049, 286–292.[Medline]
  37. Yamaguchi,R., Hirano,T., Asami,S., Chung,M.-H., Sugita,A. and Kasai,H. (1996) Increased 8-hydroxyguanine levels in DNA and its repair activity in rat kidney after administration of a renal carcinogen, ferric nitrilotriacetate. Carcinogenesis, 17, 2419–2422.[Abstract/Free Full Text]
  38. Mellon,I., Spivak,G. and Hanawalt,P.C. (1987) Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene. Cell, 51, 241–249.[ISI][Medline]
  39. Chen,R.-H., Maher,V.M., Brouwer,J., van de Putte,P. and McCormick,J.J. (1992) Preferential repair and strand-specific repair of benzo[a]pyrene diol epoxide adducts in the HPRT gene of diploid human fibroblasts. Proc. Natl Acad. Sci. USA, 89, 5413–5417.[Abstract/Free Full Text]
Received June 9, 1998; revised November 13, 1998; accepted December 3, 1998.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Am. J. Pathol.Home page
S. Akatsuka, T. T. Aung, K. K. Dutta, L. Jiang, W.-H. Lee, Y.-T. Liu, J. Onuki, T. Shirase, K. Yamasaki, H. Ochi, et al.
Contrasting Genome-Wide Distribution of 8-Hydroxyguanine and Acrolein-Modified Adenine during Oxidative Stress-Induced Renal Carcinogenesis
Am. J. Pathol., October 1, 2006; 169(4): 1328 - 1342.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
T. D. Oberley
Oxidative Damage and Cancer
Am. J. Pathol., February 1, 2002; 160(2): 403 - 408.
[Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
M. Hiroyasu, M. Ozeki, H. Kohda, M. Echizenya, T. Tanaka, H. Hiai, and S. Toyokuni
Specific Allelic Loss of p16 INK4A Tumor Suppressor Gene after Weeks of Iron-Mediated Oxidative Damage during Rat Renal Carcinogenesis
Am. J. Pathol., February 1, 2002; 160(2): 419 - 424.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Randerath, G.-D. Zhou, R. L. Somers, J. H. Robbins, and P. J. Brooks
A 32P-Postlabeling Assay for the Oxidative DNA Lesion 8,5'-Cyclo-2'-deoxyadenosine in Mammalian Tissues. EVIDENCE THAT FOUR TYPE II I-COMPOUNDS ARE DINUCLEOTIDES CONTAINING THE LESION IN THE 3' NUCLEOTIDE
J. Biol. Chem., September 14, 2001; 276(38): 36051 - 36057.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (7)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Nomoto, M.
Right arrow Articles by Kasai, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nomoto, M.
Right arrow Articles by Kasai, H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?