Effects of phenethyl isothiocyanate on metabolism and on genotoxicity of dimethylnitrosamine and 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP)

S. Knasmüller, M. D. Friesen, J. A. Holme, J. Alexander, R. Sanyal, F. Kassie, H. Bartsch

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Abstract

Phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables, inhibited the genotoxic effects of N-nitrosodimethylamine (DMN) and of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in differential DNA repair assays with E. coli K-12 strains in vitro and in animal mediated assays with mice. In Salmonella typhimurium, the mutagenic activities of DMN and PhIP measured after activation with S-9 homogenates from several organs of PEITC-treated mice were substantially lower than those obtained with homogenates of untreated animals as well. PEITC also reduced the formation of micronuclei by DMN in metabolically competent Hep-G-2 cells of human origin but was ineffective in combination with PhIP. Biochemical investigations showed that the prevention of genotoxic effects of DMN by PEITC results from an inhibition of its α-hydroxylation. The effect of oral administration of PEITC on the formation of DNA adducts of PhIP was examined in the colon and liver of mice. No inhibition of adduct formation was observed in these experiments. Biochemical experiments showed that PEITC reduces not only the metabolic activation of PhIP via 2-hydroxyamino PhIP but also inhibits a detoxification pathway (formation of 4-hydroxy PhIP). The present results can be taken as an indication that the anticarcinogenic activities of isothiocyanates towards nitrosamines are paralleled by antimutagenic effects, and that probably no such protective effects occur in combination with heterocyclic amines. Furthermore, our findings show that the effects of chemopreventive agents demonstrated in bacteria in vitro cannot always be extrapolated to reactions occurring in intact mammalian cells.

Original languageEnglish (US)
Pages (from-to)93-102
Number of pages10
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume350
Issue number1
DOIs
StatePublished - Feb 19 1996
Externally publishedYes

Bibliographical note

Funding Information:
The authors wish to thank R. Schulte Hermann for continuous support and encouragementsG. . Lep-schy for the help provided in animal experiments,E . Zohrer for technical assistancea nd evaluation of the data. T. Schut for the method of DNA extraction and L. Garren for DNA extractiona nd hydrolysis. Part of the experimental work was supportedb y the Anton Dreher grant and by a grant of the Austrian National Bank (to SK). The experimental work performed in Norway was supported by a grant (NKJ-projekt nr. 82) from the Norwegian Research Council as a part of a Nordic collaborative project under the Scandinavian Contact Agency for Agricultural Research.

Keywords

  • Anticarcinogen
  • DNA repair
  • Isothiocyanate
  • Nitrosamine

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