Comparative study of mutagenesis by O6-methylguanine in the human Ha-ras oncogene inE.coliandin vitro

Pletsa, Vasiliki; Troungos, Constantinos; Souliotis, Vassilis L.; Kyrtopoulos, Soterios A.

doi:10.1093/nar/22.19.3846

Cited by 10 publications

(5 citation statements)

References 33 publications

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“…Single-adduct studies have demonstrated that O 6 -meG is strongly premutagenic, giving rise to GC→AT transitions by direct miscoding during cell replication (26)(27)(28), a sequence change which has been found to dominate the mutation spectra induced in vitro and in vivo by S N 1 methylating agents (29)(30)(31). In the case of NDMA, sequence analysis of large numbers of mutants derived from mutagenesis in the lacI gene of Escherichia coli has shown that it induces predominantly GC→AT transitions, as well as a small proportion (~10%) of other types of mutations (30,32).…”

Section: Introductionmentioning

confidence: 99%

DNA adducts, mutant frequencies and mutation spectra in lambda lacZ transgenic mice treated with N-nitrosodimethylamine

Souliotis¹

1998

Carcinogenesis

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Groups of lambda lacZ transgenic mice were treated i.p. with N-nitrosodimethylamine (NDMA) as single doses of 5 mg/kg or 10 mg/kg or as 10 daily doses of 1 mg/kg and changes in DNA N7- or O6-methylguanine or the repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT) were followed for up to 14 days in various tissues. Adduct induction in the liver exceeded by at least one order of magnitude than observed in the next nearest target tissue (lung), and was approximately linearly related to dose, except for O6-methylguanine after the first dose of 1 mg/kg which was lower than expected. Substantial induction of lambda lacZ mutagenesis was observed only in the liver, where the mutant frequency was already maximal within 7 days after 5 mg/kg NDMA and remained unchanged thereafter up to 49 days. Small but marginally significant increases in mutant frequency were consistently observed in the spleen after all three modes of treatment. A lack of proportionality between mutation induction and the administered dose or the corresponding adduct levels was observed, probably reflecting the importance of toxicity-related cell proliferation caused by NDMA at higher doses. Twenty eight days after a dose of 10 mg/kg (causing a 3.6-fold increase in mutant frequency), NDMA was found to increase the frequency of GC-->AT mutations (with a concomitant shift of their preferential location from CpG sites to GpG sites), which made up approximately 60% of the induced mutations. Surprisingly, NDMA also caused a significant increase in deletions of a few (up to 11) base-pairs (22%).

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Section: Introductionmentioning

confidence: 99%

DNA adducts, mutant frequencies and mutation spectra in lambda lacZ transgenic mice treated with N-nitrosodimethylamine

Souliotis¹

1998

Carcinogenesis

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“…In peripheral leukocytes from healthy volunteers the median adduct concentrations were about an order of magnitude lower (range, 0.07-0.46 pmol/μmol Gua) than in liver [121,122] or colon [123]. Nevertheless, this adduct was found in 83-86% in samples of maternal and cord blood leukocyte DNA from healthy smoking and non-smoking women at levels up to 0.2 pmol/μmol guanine [124]. Interestingly, smoking status had no effect on the detected adduct levels.…”

Section: Methylationsmentioning

confidence: 83%

“…With respect to methylations, the highest yields of adducts in the target organs, such as lung, liver and nasal mucosa of rats exposed to NNK have been found for 7-methylguanine (7-mGua), followed by O 6 -methylguanine (O6-mGua), whereas very low levels of O 4 -methylthymidine (O4-mThd) were present [81]. O6-mGua Brought to you by | University of St Andrews Scotland Authenticated Download Date | 6/7/15 5:50 AM is, on the other hand, a highly pro-mutagenic adduct that gives rise to GC to AT transitions [82][83][84] of a type found in codon 12 of the Ki-ras oncogene from mouse lung tumors induced by NNK [85,86]. Some adducts from pyridyloxobutylations (HPB) have recently been identified, and include the HPB 7-and O 6 -guanines, as well as HPB O 2 -cytidine adducts [87].…”

Section: Type Of Dna Adducts From Tobacco Specific Nitrosaminesmentioning

confidence: 99%

De Minimus Non Curat Lex - Virtual Thresholds for Cancer Initiation by Tobacco Specific Nitrosamines - Prospects for Harm Reduction by Smokeless Tobacco

Nilsson

2006

International Journal of Occupational Medicine and Environmental Health

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Whereas the impact of tobacco specific nitrosamines in smokers is obscured by the presence of numerous other carcinogens and promoters, for smokeless tobacco virtually all the carcinogenic potential is associated with 4-(nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). In some countries exposure to smokeless tobacco with extremely high nitrosamine concentrations have been found to induce cancers in the head-neck region, whereas three recent large epidemiological studies failed to detect any such risk with respect to Swedish low-nitrosamine snuff. This review deals with quantitative aspects of DNA adduct formation from NNN and NNK in relation to the background levels ubiquitously found in healthy humans without known exposures to either tobacco or alkylating agents. The lack of significant increases of pro-mutagenic O6-methylations and DNA pyridyloxobutylations seen in smokers, as well as the negative outcome of the Swedish epidemiological studies, can be expected on basis of extrapolation of the dose response relationships found in rodents to actual exposures to NNK and NNN in Swedish snuff or from smoking. Sweden has the lowest prevalence of male smokers and smoking related diseases in the Western World, which has been ascribed to the fact that more than 20% of the grown up male population uses snuff. Smokeless tobacco represents an inexpensive and effective alternative to nicotine delivering products like nicotine patch, spray or gum. Considering that all other tobacco products are freely marketed, the ban on low-nitrosamine snuff in all countries in EU except Sweden is difficult to defend on either medical or ethical grounds.

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“…Another adduct generated by NDMA exposure is O 6 -methylguanine (O6-meG). This adduct is repaired by the protein O 6 -methylguanineDNA methyltransferase, and if not repaired, can produce G:C → A:T transitions (Mirsalis, Mon-forte, and Winegar 1994; Pegg 1990; Pletsa et al 1994; Rossi et al 1989; Tan, Swann, and Chance 1994). The G:C → A:T transition has been associated with an increased risk of cancer (Bedell et al 1982; Swenberg et al 1982).…”

Section: Discussionmentioning

confidence: 99%

Frequency and Spectrum of lacI Mutations in the Liver of Big Blue Mice Following the Administration of Genotoxic Carcinogens Singly and in Series

et al. 2008

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Transgenic mouse models offer a unique opportunity to study in vivo mutagenicity in any tissue of interest. In this study, the authors have determined the liver mutant frequency (MF) and mutational spectra (MS) of 12 week-old male Big Blue B6C3F1 transgenic mice exposed to the genotoxic carcinogens benzo[a]pyrene (B[a]P; 250 mg/kg/day), N-nitrosodimethylamine (NDMA; 7 mg/kg/day), or N-ethyl-1-nitrosourea (ENU; 50 mg/kg/day) singly (3 daily oral doses) or in series (B[a]P on day 1, NDMA on day 2, and ENU on day 3). All genotoxic agents, alone or in series, increased MF in the liver (three- to sixfold). MS analyses of liver DNA revealed a high percentage of G:C --> A:T transitions in the control (88%) and the NDMA (64%) groups. In contrast, B[a]P, ENU, and the series treatment induced a high percentage (> or = 50%) of transversions. Significantly, 46% (19 out of 41) of the mutations in the series treatment group occurred at CpG dinucleotides, compared to less than 22% in the other treatment groups. The MS from the series exposure was most similar to B[a]P with a high percentage of transversion mutations occurring at guanine nucleotides (36%). These preliminary data suggest that genotoxic carcinogens, when exposed in series, produce a unique MS profile characterized not only by shifts in mutation class but also sequence context.

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Comparative study of mutagenesis by O⁶-methylguanine in the human Ha-ras oncogene inE.coliandin vitro

Cited by 10 publications

References 33 publications

DNA adducts, mutant frequencies and mutation spectra in lambda lacZ transgenic mice treated with N-nitrosodimethylamine

DNA adducts, mutant frequencies and mutation spectra in lambda lacZ transgenic mice treated with N-nitrosodimethylamine

De Minimus Non Curat Lex - Virtual Thresholds for Cancer Initiation by Tobacco Specific Nitrosamines - Prospects for Harm Reduction by Smokeless Tobacco

Frequency and Spectrum of lacI Mutations in the Liver of Big Blue Mice Following the Administration of Genotoxic Carcinogens Singly and in Series

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