PMID- 24066836
OWN - NLM
STAT- MEDLINE
DCOM- 20140526
LR  - 20211021
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Print)
IS  - 0893-228X (Linking)
VI  - 26
IP  - 10
DP  - 2013 Oct 21
TI  - Role of aldehydes in the toxic and mutagenic effects of nitrosamines.
PG  - 1464-73
LID - 10.1021/tx400196j [doi]
AB  - alpha-Hydroxynitrosamine metabolites of nitrosamines decompose to a reactive 
      diazohydroxide and an aldehyde. To test the hypothesis that the aldehydes 
      contribute to the harmful effects of nitrosamines, the toxic and mutagenic 
      activities of three model methylating agents were compared in Chinese hamster 
      ovary cells expressing or not expressing human O(6)-alkylguanine DNA 
      alkyltransferase (AGT). N-Nitrosomethylurethane (NMUr), 
      acetoxymethylmethylnitrosamine (AMMN), and 
      4-(methylnitrosamino)-4-acetoxy-1-(3-pyridyl)-1-butanone (NNK-4-OAc) are all 
      activated by ester hydrolysis to methanediazohydroxide. NMUr does not form an 
      aldehyde, whereas AMMN generates formaldehyde, and NNK-4-OAc produces 
      4-oxo-1-(3-pyridyl)-1-butanone (OPB). Since these compounds were likely to 
      alkylate DNA to different extents, the toxic and mutagenic activities of these 
      compounds were normalized to the levels of the most cytotoxic and mutagenic DNA 
      adduct, O(6)-mG, to assess if the aldehydes contributed to the toxicological 
      properties of these methylating agents. Levels of 7-mG indicated that the 
      differences in cytotoxic and mutagenic effects of these compounds resulted from 
      differences in their ability to methylate DNA. When normalized against the levels 
      of O(6)-mG, there was no difference between these three compounds in cells that 
      lacked AGT. However, AMMN and NNK-4-OAc were more toxic than NMUr in cells 
      expressing AGT when normalized against O(6)-mG levels. In addition, AMMN was more 
      mutagenic than NNK-4-OAc and MNUr in these cells. These findings demonstrate that 
      the aldehyde decomposition products of nitrosamines can contribute to the 
      cytotoxic and/or mutagenic activity of methylating nitrosamines.
FAU - Peterson, Lisa A
AU  - Peterson LA
AD  - Division of Environmental Health Sciences and Masonic Cancer Center, University 
      of Minnesota , Minneapolis, Minnesota 55455, United States.
FAU - Urban, Anna M
AU  - Urban AM
FAU - Vu, Choua C
AU  - Vu CC
FAU - Cummings, Meredith E
AU  - Cummings ME
FAU - Brown, Lee C
AU  - Brown LC
FAU - Warmka, Janel K
AU  - Warmka JK
FAU - Li, Li
AU  - Li L
FAU - Wattenberg, Elizabeth V
AU  - Wattenberg EV
FAU - Patel, Yesha
AU  - Patel Y
FAU - Stram, Daniel O
AU  - Stram DO
FAU - Pegg, Anthony E
AU  - Pegg AE
LA  - eng
GR  - R01 CA115309/CA/NCI NIH HHS/United States
GR  - P30 CA077598/CA/NCI NIH HHS/United States
GR  - R01 CA059887/CA/NCI NIH HHS/United States
GR  - CA-138338/CA/NCI NIH HHS/United States
GR  - CA-059887/CA/NCI NIH HHS/United States
GR  - P30 CA-77598/CA/NCI NIH HHS/United States
GR  - R37 CA018137/CA/NCI NIH HHS/United States
GR  - CA-018137/CA/NCI NIH HHS/United States
GR  - P01 CA138338/CA/NCI NIH HHS/United States
GR  - CA-115309/CA/NCI NIH HHS/United States
GR  - R01 CA018137/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130925
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Aldehydes)
RN  - 0 (DNA Adducts)
RN  - 0 (Nitrosamines)
RN  - 0 (Pyrazines)
RN  - 103829-56-7 (pyrazine-2-diazohydroxide)
RN  - 56856-83-8 (methyl(acetoxymethyl)nitrosamine)
RN  - 615-53-2 (Nitrosomethylurethane)
RN  - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase)
RN  - M43H21IO8R (Dimethylnitrosamine)
SB  - IM
MH  - Aldehydes/chemistry/metabolism/*toxicity
MH  - Animals
MH  - CHO Cells
MH  - Cricetinae
MH  - Cricetulus
MH  - DNA Adducts/analysis/metabolism
MH  - DNA Damage/*drug effects
MH  - DNA Methylation/drug effects
MH  - Dimethylnitrosamine/analogs & derivatives/chemistry/metabolism/toxicity
MH  - Humans
MH  - Models, Chemical
MH  - Mutagenicity Tests
MH  - Nitrosamines/chemistry/*metabolism/toxicity
MH  - Nitrosomethylurethane/chemistry/metabolism/toxicity
MH  - O(6)-Methylguanine-DNA Methyltransferase/genetics/metabolism
MH  - Pyrazines/chemistry/metabolism
PMC - PMC3835663
MID - NIHMS527794
EDAT- 2013/09/27 06:00
MHDA- 2014/05/27 06:00
PMCR- 2014/10/21
CRDT- 2013/09/27 06:00
PHST- 2013/09/27 06:00 [entrez]
PHST- 2013/09/27 06:00 [pubmed]
PHST- 2014/05/27 06:00 [medline]
PHST- 2014/10/21 00:00 [pmc-release]
AID - 10.1021/tx400196j [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2013 Oct 21;26(10):1464-73. doi: 10.1021/tx400196j. Epub 2013 
      Sep 25.