Mutagenicity of N-nitrosodiethanolamine and its acetyl derivatives

Gilbert, P.; Fabry, L.; Rollmann, Bruno; Lombart, P.; Rondelet, J; Poncelet, F.; Léonard, A.; Mercier, Michel

doi:10.1016/0165-1218(81)90240-8

Cited by 17 publications

(1 citation statement)

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“…Nitrosamines, such as methylethanolnitrosamine ( 1 ) and N- nitrosodiethanolamine ( 2 ), derived from common commercial alkanolamines, are widespread environmental trace contaminants , exhibiting considerable carcinogenicity. − While common diakylnitrosamines appear to undergo carcinogenic activation through enzymatic α-hydroxylation as shown in Scheme for dimethylnitrosamine, a process which leads to DNA alkylation, there are serious questions regarding the applicability of this pathway to alkanolnitrosamines such as 1 or 2 . Numerous investigators have probed the microsomal-mediated metabolic activation of N- nitrosodiethanolamine ( 2 ) − to a mutagen and have failed to observe any mutagenicity, strongly suggesting that this compound is not a substrate for the cytochrome P-450 enzymes which are responsible for the conversion of 3 to 4 (Scheme ), for example. ,− Similar preparations have also failed to produce any evidence for metabolic conversions of 2 14 and have led to several different hypotheses regarding the mode of activation of these compounds. At least three different biochemical activation schemes are under active consideration: (a) conversion of the β-nitrosamino alcohol into reactive aldehydes by alcohol dehydrogenase-mediated oxidation, − ,− (b) enzymatic sulfate ester formation (sulfation) of the hydroxyl group to generate a compound which undergoes N- nitroso oxygen neighboring group assisted solvolysis to generate alkylating agents, ,− and (c) chain-shortening reactions to generate methyl-substituted nitrosamines which are substrates for cytochrome P-450 enzymes. − The work presented here is principally directed at testing parts of the sulfation mode of activation which foresees the generation of a 3-methyl-1,2,3-oxadiazolinium ion 10 (Scheme…”

Section: Introductionmentioning

confidence: 99%

DNA Guanine Adducts from 3-Methyl-1,2,3-oxadiazolinium Ions

Loeppky

et al. 1996

J. Am. Chem. Soc.

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The reaction of 3-methyl-1,2,3-oxadiazolinium tosylate 10, a close model for a putative reactive intermediate in the carcinogenic activation of ethanol nitrosamines such as (2-hydroxyethyl)methylnitrosamine 1, with various guanine derivatives, including acycloguanosine 12, deoxyguanosine, deoxyguanosine monophosphate, and cyclic guanosine monophosphate, various DNA oligomers, and calf-thymus DNA has been examined to determine whether this compound methylates and hydroxyethylates guanine residues as proposed. In all of the transformations, 7-(2-(methylnitrosamino)ethyl)guanine (14) is the major product, following acidic hydrolysis, and exceeds the formation of 7-methylguanine by ratios ranging from 4:1 to 48:1, depending upon the guanine bearing substrate. O 6-(2-(Methylnitrosamino)ethyl)deoxyguanosine (20) was prepared from the Mitsunobu coupling of 1 and a protected deoxyguanosine derivative. 20 is not produced in the reaction of 10 and deoxyguanosine and decomposes to 1 and guanine upon mild acid treatment, suggesting possible neighboring group participation in its facile hydrolytic cleavage. All of the major products from the reaction of 10 and 12 have been characterized, including the direct alkylation product, 7-(2-(methylnitrosamino)ethyl)acycloguanosine (13), and N 2-(2-(methylnitrosamino)ethyl)guanine, which was independently synthesized. Elucidation of the reactions of DNA with 10 and other electrophiles was facilitated by the development of both partial and total enzymatic hydrolysis assays utilizing 32P-5‘-labeled DNA oligotetramers containing one of each base type and HPLC with radiometric detection. The partial hydrolysis assay gives information as to the type of base being modified, and the total hydrolysis assay permits a determination of the number of adducts produced for a given base. The assays permit a comparison between reactions where the same type of base adduct could be expected. Comparisons of the reactions of ethylene oxide and 10 using this methodology showed that 10 does not hydroxyethylate guanine in DNA.

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Section: Introductionmentioning

confidence: 99%

DNA Guanine Adducts from 3-Methyl-1,2,3-oxadiazolinium Ions

Loeppky

et al. 1996

J. Am. Chem. Soc.

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N ‐Nitroso‐2,2′‐Iminodiethanoldiacetate 13256‐19‐4

2004

Sax's Dangerous Properties of Industrial Materials

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Dose response study of N‐nitrosodiethanolamine initiation of rat hepatocarcinogenesis

Ogawa¹,

Hasegawa²,

Wada³

et al. 1991

Teratog Carcinog Mutagen

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Initiating activity of N-nitrosodiethanolamine (NDELA) for rat liver carcinogenesis was investigated using an 8-weeks bioassay system. Male F344 rats were initially treated with a single intraperitoneal injection of NDELA at one of five dose levels: 1,600, 800, 400, 200, or 100 mg/kg. Two weeks later, the rats were placed on 0.02% 2-acetylaminofluorene (2-AAF) or 0.05% phenobarbital (PB) containing diet for 6 weeks. All animals were subjected to 2/3 partial hepatectomy 4 weeks after the NDELA treatment, and killed at the end of the eighth week. NDELA itself exerted low toxicity in terms of body weight gain. Clear dose-dependent initiating activity of NDELA was observed in terms of development of glutathione S-transferase placental form (GST-P) positive liver cell foci, this being more apparent with PB promotion than with 2-AAF where the enhancing regimen itself caused multiple lesion development. Initiating potential of NDELA, however, was much lower than that observed for diethylnitrosamine in our previous work.

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Mutagenicity of N-nitrosodiethanolamine and its acetyl derivatives

Cited by 17 publications

References 16 publications

DNA Guanine Adducts from 3-Methyl-1,2,3-oxadiazolinium Ions

DNA Guanine Adducts from 3-Methyl-1,2,3-oxadiazolinium Ions

N ‐Nitroso‐2,2′‐Iminodiethanoldiacetate 13256‐19‐4

Dose response study of N‐nitrosodiethanolamine initiation of rat hepatocarcinogenesis

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