Comparative tumorigenicity of N-nitroso-2-hydroxymorpholine, N-nitrosodiethanolamine and N-nitrosomorpholine in A/J mice and F344 rats

Hecht, Stephen S.; Lijinsky, William; Kovatch, Robert M.; Chung, Fung‐Lung; Saavedra, Jose E.

doi:10.1093/carcin/10.8.1475

Cited by 27 publications

(22 citation statements)

References 19 publications

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“…The latter paths are expected to lead to carcinogenesis. Such a phenomenon, that is, further oxidation of NHMOR at carbons 3 or 5 before it escapes from the P450 active site, could explain why Hecht et al failed to observe carcinogenic activity for orally administered NHMOR (77). It is possible that most of this material is detoxified by cytosolic enzymes before it reaches the endoplasmic reticulum where high concentrations of P450 are located.…”

Section: Methodsmentioning

confidence: 99%

Microsome-Mediated Oxidation of N-Nitrosodiethanolamine (NDELA), a Bident Carcinogen

Loeppky

Goelzer

2002

Chem. Res. Toxicol.

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N-Nitrosodiethanolamine (NDELA), an environmentally prevalent, potent carcinogen, undergoes competitive rat liver microsome-mediated oxidation at both the alpha (adjacent to N)- and beta-positions of the 2-hydroxyethyl chains. The former process, alpha-hydroxylation, is detected by the formation of glycolaldehyde (determined as its 2,4-dinitrophenylhydrazone DNP) that is assumed to arise from the decomposition of the corresponding alpha-hydroxynitrosamine, which is also the progenitor of the 2-hydroxyethyldiazonium ion. This finding refutes prior published work that states that the alpha-hydroxylation of NDELA does not occur. Competitive microsomal oxidation at the beta-position gives the hemiacetal N-nitroso-2-hydroxymorpholine (NHMOR) at a rate 1.5 times alpha-hydroxylation. Glycolaldehyde is oxidized in this system to glyoxal at a rate 39 times the conversion of NDELA to glycolaldehyde. The alpha-hydroxylation of NHMOR at either C-3 or C-5 to give glyoxal or glycolaldehyde, respectively, occurs at respective rates 3-6 times that of the alpha-hydroxylation of NDELA. Ethylene glycol, a hydrolysis product of the 2-hydroxyethyldiazonium ion is shown to undergo microsome mediate oxidation to glyoxal. Ethyl-2-hydroxyethylnitrosamine (NEELA) undergoes a similar set of microsome-mediated oxidations at alpha-position of the ethyl (fastest) and 2-hydroxyethyl groups, as well as beta-oxidation of the 2-hydroxyethyl group, a process which is slightly more rapid than alpha-hydroxylation of the same chain. Comparisons of oxidations rates of these substrates, as manipulated by preinducers, isoniazid, streptozocin, and phenobarbital, and enzyme inhibitors diethyldithiocarbamate and 4-methylpyrazole, with that of dimethylnitrosamine, a substrate for cytochrome P450 2E1, strongly suggest that this isozyme is also responsible for the oxidations reported here. alpha-Deuteration of NDELA practically eliminates its alpha-hydroxylation by microsomes from isoniazid induced rats, but doubles beta-oxidation, while beta-deuteration of this substrate significantly reduces beta-oxidation and enhances alpha-hydroxylation. Since both glyoxal-guanine and 2-hydroxyethyl-DNA base adducts are known to arise from the in vivo administration of NDELA and because this work demonstrates that these two fragments can come from the microsomal oxidation of a single nitrosamine molecule containing the 2-hydroxyethyl group, NDELA and related nitrosamines are bident (two-toothed) carcinogens, a process which is likely to enhance their carcinogenic potency.

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Section: Methodsmentioning

confidence: 99%

Microsome-Mediated Oxidation of N-Nitrosodiethanolamine (NDELA), a Bident Carcinogen

Loeppky

Goelzer

2002

Chem. Res. Toxicol.

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“…The most significant challenge to the β-oxidation pathway comes from carcinogenesis experiments utilizing NHMOR. Lijinsky and Hecht found that NHMOR is not carcinogenic in F344 rats and only weakly carcinogenic in A/J mice (44). While it can be argued that administration of NHMOR in the drinking water does not result in its arrival at the proper compartment in the liver to elicit its carcinogenic action, its lack of carcinogenicity, and additional confounding factors presented above, raise doubts regarding the β-oxidation hypothesis and the mode of NDELA carcinogenic activation.…”

Section: Introductionmentioning

confidence: 99%

Probing the Mechanism of the Carcinogenic Activation of N-Nitrosodiethanolamine with Deuterium Isotope Effects: In Vivo Induction of DNA Single-Strand Breaks and Related in Vitro Assays

Loeppky

Fuchs

Janzowski

et al. 1998

Chem. Res. Toxicol.

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A series of bioassays, including in vivo induction of DNA single-strand breaks (SSB) and cytotoxicity in cytochrome P450 2E1-transfected cells, were utilized with N-nitrosodiethanolamine (NDELA), its deuterated isotopomers (alpha-D4NDELA and beta-D4NDELA), N-nitroso-2-hydroxymorpholine (NHMOR), and two of its deuterated isotopomers (2-D-NHMOR and 5,5-D2-NHMOR) to probe the mechanism of carcinogenic activation of NDELA and the role of its metabolite NHMOR. DNA samples, taken from the livers of male Wistar rats 4 h after the administration of NDELA, exhibited dose-dependent DNA SSB levels over the range of 0.08-0.75 mmol/kg (body weight), with the greatest SSB level at the highest dose. Deuterium isotope effects on DNA SSB levels were inversely dependent on dose: alpha-D4NDELA, 3. 22-1.37; and beta-D4NDELA, 1.38-0.79. At the lowest dose of 0.15 mmol/kg (body weight), 5,5-D2-NHMOR gave an isotope effect for DNA SSB of 2.8 while that for 2-D-NHMOR was 0.7. NDELA and beta-D4NDELA were equally cytotoxic to human P450 2E1-transfected V79 Chinese hamster cells, while alpha-D4NDELA was not. Significant DNA SSB levels were observed in these cells for NDELA and beta-D4NDELA but not for alpha-D4NDELA. A kinetic deuterium isotope effect of 2.6 for Vmax/Km was observed for the horse liver alcohol dehydrogenase-mediated oxidation of beta-D4NDELA to NHMOR, while kH/kD for alpha-D4NDELA was 1.05. These data provide the first definitive evidence for the activation of NDELA by a pathway involving the scission of the alpha-CH bond and are consistent with P450 2E1-mediated alpha-hydroxylation of NDELA producing the corresponding reactive alpha-hydroxynitrosamine.

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“…For example, via the oral route the main target organ of NMPA and NMBA is the esophagus in rats (Lijinsky et al, 1983) while it is the liver in the hamster . Furthermore, the main target organ of NDELA via the oral route in the rat is the liver, while in the mouse it is the lung (Hecht et al, 1989).…”

Section: Target-organs Of Tumor Formationmentioning

confidence: 99%

Hazard assessment of nitrosamine and nitramine by-products of amine-based CCS: Alternative approaches

Buist

DeVito

Goldbohm

et al. 2015

Regulatory Toxicology and Pharmacology

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Comparative tumorigenicity of N-nitroso-2-hydroxymorpholine, N-nitrosodiethanolamine and N-nitrosomorpholine in A/J mice and F344 rats

Cited by 27 publications

References 19 publications

Microsome-Mediated Oxidation of N-Nitrosodiethanolamine (NDELA), a Bident Carcinogen

Microsome-Mediated Oxidation of N-Nitrosodiethanolamine (NDELA), a Bident Carcinogen

Probing the Mechanism of the Carcinogenic Activation of N-Nitrosodiethanolamine with Deuterium Isotope Effects: In Vivo Induction of DNA Single-Strand Breaks and Related in Vitro Assays

Hazard assessment of nitrosamine and nitramine by-products of amine-based CCS: Alternative approaches

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