Effects of cytosol on mutagenesis induced by N-nitrosodimethylamine, N-nitrosomethylurea and α-acetoxy-N-nitrosodimethylamine in different strains of Salmonella

Evidence for different ultimate mutagens from N-nitrosodimethylmine

Research output: Contribution to journalArticle

Abstract

N-Nitrosodimethylamine (NDMA), but not N-nitroso-N-methylurea (MNU) was more mutagenic in the Salmonella hisG428 strain, TA104, than in the hisG46 strain, TA100 in the presence of rat or hamster liver S-9 mix. As both NDMA and MNU can give rise to methyldiazonium ion (MDI) it appears that NDMA can be metabolized to an additional mutagen with a higher activity in TA104. The effects of W and error-prone repair on NDMA and MNU-induced mutagenesis in TA104 were also different. α-Acetoxy-NDMA, which gives rise to the NDMA metabolite, α-hydroxy-NDMA, was more mutagenic in TA104 than TA100, under certain conditions. Several metabolites of NDMA (formaldehyde, 1,1-dimethylhydrazine and nitrite) were not significantly mutagenic at the concentrations that could have been generated from NDMA. It was previously reported that the microsomal-mediated mutagenesis induced by NDMA is greatly increased by cytosol in TA104, but not in TA100. The current study found that when cytosol was separated into a high and a low mol. wt fraction, neither greatly enhanced microsomal-mediated mutagenesis by NDMA in TA104. Addition of NAD to the high, but not the low mol. vt fraction resulted in greatly enhanced activation of NDMA to a mutagen in TA104. The enhancement by cytosol of NDMA-induced mutagenesis in hisG428 was only observed when both microsomes and cytosol were simultaneously present. These observations indicate that (i) the precursor to the ultimate mutagen is relatively short-lived; and (ii) the metabolism of α-hydroxy-NDMA to a secondary mutagenic metabolite, possibly N-nitroso-N-methylformamide, by alcohol dehydrogenase may be responsible for the ultimate mutagen with relatively high activity in TA104.

Original languageEnglish (US)
Pages (from-to)1013-1019
Number of pages7
JournalCarcinogenesis
Volume14
Issue number5
StatePublished - 1993

Fingerprint

Mutagens
Methylnitrosourea
Dimethylnitrosamine
Mutagenesis
Salmonella
Cytosol
Metabolites
Alcohol
Precursor
Metabolism
Liver
Repair
Activation
Enhancement
Formaldehyde
Rats
Alcohols
Chemical activation
methylformamide
Evidence

ASJC Scopus subject areas

  • Cancer Research
  • Physiology
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Behavioral Neuroscience

Cite this

@article{ee7a3edece2a4fc1b07ac55e9e1e9b0c,
title = "Effects of cytosol on mutagenesis induced by N-nitrosodimethylamine, N-nitrosomethylurea and α-acetoxy-N-nitrosodimethylamine in different strains of Salmonella: Evidence for different ultimate mutagens from N-nitrosodimethylmine",
abstract = "N-Nitrosodimethylamine (NDMA), but not N-nitroso-N-methylurea (MNU) was more mutagenic in the Salmonella hisG428 strain, TA104, than in the hisG46 strain, TA100 in the presence of rat or hamster liver S-9 mix. As both NDMA and MNU can give rise to methyldiazonium ion (MDI) it appears that NDMA can be metabolized to an additional mutagen with a higher activity in TA104. The effects of W and error-prone repair on NDMA and MNU-induced mutagenesis in TA104 were also different. α-Acetoxy-NDMA, which gives rise to the NDMA metabolite, α-hydroxy-NDMA, was more mutagenic in TA104 than TA100, under certain conditions. Several metabolites of NDMA (formaldehyde, 1,1-dimethylhydrazine and nitrite) were not significantly mutagenic at the concentrations that could have been generated from NDMA. It was previously reported that the microsomal-mediated mutagenesis induced by NDMA is greatly increased by cytosol in TA104, but not in TA100. The current study found that when cytosol was separated into a high and a low mol. wt fraction, neither greatly enhanced microsomal-mediated mutagenesis by NDMA in TA104. Addition of NAD to the high, but not the low mol. vt fraction resulted in greatly enhanced activation of NDMA to a mutagen in TA104. The enhancement by cytosol of NDMA-induced mutagenesis in hisG428 was only observed when both microsomes and cytosol were simultaneously present. These observations indicate that (i) the precursor to the ultimate mutagen is relatively short-lived; and (ii) the metabolism of α-hydroxy-NDMA to a secondary mutagenic metabolite, possibly N-nitroso-N-methylformamide, by alcohol dehydrogenase may be responsible for the ultimate mutagen with relatively high activity in TA104.",
author = "Joseph Guttenplan",
year = "1993",
language = "English (US)",
volume = "14",
pages = "1013--1019",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "5",

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TY - JOUR

T1 - Effects of cytosol on mutagenesis induced by N-nitrosodimethylamine, N-nitrosomethylurea and α-acetoxy-N-nitrosodimethylamine in different strains of Salmonella

T2 - Evidence for different ultimate mutagens from N-nitrosodimethylmine

AU - Guttenplan, Joseph

PY - 1993

Y1 - 1993

N2 - N-Nitrosodimethylamine (NDMA), but not N-nitroso-N-methylurea (MNU) was more mutagenic in the Salmonella hisG428 strain, TA104, than in the hisG46 strain, TA100 in the presence of rat or hamster liver S-9 mix. As both NDMA and MNU can give rise to methyldiazonium ion (MDI) it appears that NDMA can be metabolized to an additional mutagen with a higher activity in TA104. The effects of W and error-prone repair on NDMA and MNU-induced mutagenesis in TA104 were also different. α-Acetoxy-NDMA, which gives rise to the NDMA metabolite, α-hydroxy-NDMA, was more mutagenic in TA104 than TA100, under certain conditions. Several metabolites of NDMA (formaldehyde, 1,1-dimethylhydrazine and nitrite) were not significantly mutagenic at the concentrations that could have been generated from NDMA. It was previously reported that the microsomal-mediated mutagenesis induced by NDMA is greatly increased by cytosol in TA104, but not in TA100. The current study found that when cytosol was separated into a high and a low mol. wt fraction, neither greatly enhanced microsomal-mediated mutagenesis by NDMA in TA104. Addition of NAD to the high, but not the low mol. vt fraction resulted in greatly enhanced activation of NDMA to a mutagen in TA104. The enhancement by cytosol of NDMA-induced mutagenesis in hisG428 was only observed when both microsomes and cytosol were simultaneously present. These observations indicate that (i) the precursor to the ultimate mutagen is relatively short-lived; and (ii) the metabolism of α-hydroxy-NDMA to a secondary mutagenic metabolite, possibly N-nitroso-N-methylformamide, by alcohol dehydrogenase may be responsible for the ultimate mutagen with relatively high activity in TA104.

AB - N-Nitrosodimethylamine (NDMA), but not N-nitroso-N-methylurea (MNU) was more mutagenic in the Salmonella hisG428 strain, TA104, than in the hisG46 strain, TA100 in the presence of rat or hamster liver S-9 mix. As both NDMA and MNU can give rise to methyldiazonium ion (MDI) it appears that NDMA can be metabolized to an additional mutagen with a higher activity in TA104. The effects of W and error-prone repair on NDMA and MNU-induced mutagenesis in TA104 were also different. α-Acetoxy-NDMA, which gives rise to the NDMA metabolite, α-hydroxy-NDMA, was more mutagenic in TA104 than TA100, under certain conditions. Several metabolites of NDMA (formaldehyde, 1,1-dimethylhydrazine and nitrite) were not significantly mutagenic at the concentrations that could have been generated from NDMA. It was previously reported that the microsomal-mediated mutagenesis induced by NDMA is greatly increased by cytosol in TA104, but not in TA100. The current study found that when cytosol was separated into a high and a low mol. wt fraction, neither greatly enhanced microsomal-mediated mutagenesis by NDMA in TA104. Addition of NAD to the high, but not the low mol. vt fraction resulted in greatly enhanced activation of NDMA to a mutagen in TA104. The enhancement by cytosol of NDMA-induced mutagenesis in hisG428 was only observed when both microsomes and cytosol were simultaneously present. These observations indicate that (i) the precursor to the ultimate mutagen is relatively short-lived; and (ii) the metabolism of α-hydroxy-NDMA to a secondary mutagenic metabolite, possibly N-nitroso-N-methylformamide, by alcohol dehydrogenase may be responsible for the ultimate mutagen with relatively high activity in TA104.

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M3 - Article

VL - 14

SP - 1013

EP - 1019

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

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