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Mutagenicity of N-nitrosodiethanolamine in a V79-derived cell line expressing two human biotransformation enzymes

Yungang Liu1, Hansruedi Glatt

  • 1German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Department of Nutritional Toxicology, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. yungang1@hotmail.com

Mutation Research
|July 12, 2008
PubMed

Insights

N-nitrosodiethanolamine (NDELA) causes gene mutations in mammalian cells, but only when the human enzyme cytochrome P450 2E1 (CYP2E1) is present. This finding explains NDELA's weak genotoxicity in standard tests.

Area of Science:

  • Toxicology
  • Genetics
  • Biochemistry

Background:

  • N-nitrosodiethanolamine (NDELA) is a carcinogen in rodents but shows weak genotoxicity in vitro.
  • NDELA activation may require specific enzymes like cytochrome P450 2E1 (CYP2E1) and sulphotransferases (SULTs).

Purpose of the Study:

  • To investigate the role of human CYP2E1 and SULT1A1 in NDELA-induced genotoxicity.
  • To elucidate the mechanism behind NDELA's poor in vitro genotoxicity response.

Main Methods:

  • Gene mutation assays were performed in V79 cells engineered to express human CYP2E1 and SULT1A1.
  • Inhibitors of CYP2E1 (1-aminobenzotriazole) and SULT1A1 (pentachlorophenol) were used to assess enzyme involvement.
  • The activity of NDELA and reference mutagens was evaluated in parental and engineered V79 cells.

Main Results:

  • NDELA induced concentration-dependent gene mutations at the hprt locus in V79-hCYP2E1-hSULT1A1 cells, but not in parental V79 cells.
  • NDELA-induced mutagenicity was abolished by the CYP2E1 inhibitor, indicating CYP2E1 is crucial for activation.
  • The SULT1A1 inhibitor did not affect NDELA mutagenicity, showing SULT1A1 is not involved in activation or inactivation in this model.

Conclusions:

  • Human CYP2E1 is essential for activating NDELA to induce gene mutations in mammalian cells.
  • Human SULT1A1 does not play a significant role in NDELA activation or inactivation.
  • This study provides the first evidence of NDELA inducing gene mutations in mammalian cells via CYP2E1-mediated activation.

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