In vivo and in vitro genotoxicity of several N-nitrosamines in extrahepatic tissues of the rat

S. Y. Brendler, A. Tompa, K. F. Hutter, R. Preussmann, B. L. Pool-Zobel

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Toxicological mechanisms involved in organotropism of tumor induction may include cell-specific metabolic activation of the carcinogen, in vivo distribution of active metabolites and persistance of induced DNA damage. In order to elucidate which factors are involved in the organotropic action of environmentally relevant N-nitrosamines, we have studied their genotoxic and cytotoxic effects within primary intact cells of lung and kidney. The end-points determined were cytotoxicity by trypan blue exclusion and DNA single-strand break (SSB) induction by alkaline filter elution. The assays were performed in vitro to determine organ-specific metabolic activation by incubating the cells with the test compounds. The results obtained with N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiethanolamine (NDElA), N-nitrosoethylvinylamine (NEVA), N-nitrosodibutylamine (NDBA), N-nitrosobutylbutanolamine (NBBOH), N-nitrosobutylcarboxypropylamine (BCPN), N-nitrosomethylbenzylamine (NMBzA) and N-nitrosodibenzylamine (NDBzA) indicate that several compounds may be activated to reactive metabolites by cells of kidney and lung, NDBzA revealing the highest degree of cytotoxicity. In contrast, genotoxicity in kidney cells was induced only by NBBOH and BCPN and at relative low levels. Primary lung cells could not be employed as indicators for genotoxic effects in vitro because the cell yield was not sufficient to perform the alkaline elution assay. To assess the distribution of NDMA in the whole rat and the persistence of the induced DNA damage in the two organs, further studies were carried out after oral application of 1, 2, 4, 10, 20, 32 and 40 mg/kg to the animals. Following 1 h exposure of rats to NDMA, the lowest effective genotoxic dose for lung and kidney was 2 mg NDMA/kg body wt. A plateau was achieved after a dose of 20 mg/kg in both organs. Furthermore, the persistence of DNA damage was studied in the lung. After 4 h exposure, DNA damage was still detectable at 32 mg NDMA/kg, but for the lower doses it was reduced nearly to control levels. After 16 h exposure the SSB rate in lung cells was reduced for all dose levels except for the highest dose of 40 mg/kg.

Original languageEnglish
Pages (from-to)2435-2441
Number of pages7
JournalCarcinogenesis
Volume13
Issue number12
Publication statusPublished - Dec 1992

Fingerprint

Nitrosamines
Rats
Dimethylnitrosamine
DNA
Lung
Tissue
butyl(3-carboxypropyl)nitrosamine
Cell
Kidney
Dose
DNA Damage
Cytotoxicity
Metabolites
Damage
Assays
N-nitrosodibenzylamine
dibutylnitrosamine
Chemical activation
nitrosobenzylmethylamine
Carcinogens

ASJC Scopus subject areas

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

Cite this

Brendler, S. Y., Tompa, A., Hutter, K. F., Preussmann, R., & Pool-Zobel, B. L. (1992). In vivo and in vitro genotoxicity of several N-nitrosamines in extrahepatic tissues of the rat. Carcinogenesis, 13(12), 2435-2441.

In vivo and in vitro genotoxicity of several N-nitrosamines in extrahepatic tissues of the rat. / Brendler, S. Y.; Tompa, A.; Hutter, K. F.; Preussmann, R.; Pool-Zobel, B. L.

In: Carcinogenesis, Vol. 13, No. 12, 12.1992, p. 2435-2441.

Research output: Contribution to journalArticle

Brendler, SY, Tompa, A, Hutter, KF, Preussmann, R & Pool-Zobel, BL 1992, 'In vivo and in vitro genotoxicity of several N-nitrosamines in extrahepatic tissues of the rat', Carcinogenesis, vol. 13, no. 12, pp. 2435-2441.
Brendler SY, Tompa A, Hutter KF, Preussmann R, Pool-Zobel BL. In vivo and in vitro genotoxicity of several N-nitrosamines in extrahepatic tissues of the rat. Carcinogenesis. 1992 Dec;13(12):2435-2441.
Brendler, S. Y. ; Tompa, A. ; Hutter, K. F. ; Preussmann, R. ; Pool-Zobel, B. L. / In vivo and in vitro genotoxicity of several N-nitrosamines in extrahepatic tissues of the rat. In: Carcinogenesis. 1992 ; Vol. 13, No. 12. pp. 2435-2441.
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