Role of aldehydes in the toxic and mutagenic effects of nitrosamines.
α-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 O⁶-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, O⁶-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 O⁶-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 O⁶-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.
Division of Environmental Health Sciences and Masonic Cancer Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Lisa A
LA
Peterson
Anna M
AM
Urban
Choua C
CC
Vu
Meredith E
ME
Cummings
Lee C
LC
Brown
Janel K
JK
Warmka
Li
L
Li
Elizabeth V
EV
Wattenberg
Yesha
Y
Patel
Daniel O
DO
Stram
Anthony E
AE
Pegg
D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018736:DNA Adducts / Q000032:analysis / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D019175:DNA Methylation / Q000187:drug effects; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D008956:Models, Chemical; D009152:Mutagenicity Tests; D009602:Nitrosamines / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D009605:Nitrosomethylurethane / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000737:chemistry / Q000378:metabolism
D000447:Aldehydes; D018736:DNA Adducts; D009602:Nitrosamines; D011719:Pyrazines; C051397:pyrazine-2-diazohydroxide; C014659:methyl(acetoxymethyl)nitrosamine; D009605:Nitrosomethylurethane; D019853:O(6)-Methylguanine-DNA Methyltransferase; D004128:Dimethylnitrosamine