Evaluation of genetic toxicity of 6-diazo-5-oxo-l-norleucine (DON)

Rohan M. Kulkarni, Emily W. Dakoulas, Kenneth Miller, Pramod S. Terse

Research output: Contribution to journalArticle

Abstract

DON (6-diazo-5-oxo-l-norleucine), a glutamine antagonist, was demonstrated to exhibit analgesic, antibacterial, antiviral and anticancer properties. The study was performed to characterize its in vitro and in vivo genetic toxicity potential. DON was tested in the bacterial reverse mutation assay (Ames test) using Salmonella typhimurium tester strains (TA98, TA100, TA1535 and TA1537) and Escherichia coli tester strain (WP2 uvrA) with and without S9 and also with reductive S9. In addition, DON was tested for the chromosome aberrations in Chinese hamster ovary (CHO) cells with or without S9 to evaluate the clastogenic potential. Furthermore, DON was also evaluated for its in vivo clastogenic activity by detecting micronuclei in polychromatic erythrocyte (PCE) cells in bone marrow collected from the male mice dosed intravenously with 500, 100, 10, 1 and 0.1 mg/kg at 24 and 48-h post-dose. The Ames mutagenicity assay showed no positive mutagenic responses. However, the in vitro chromosome aberration assay demonstrated dose dependent statistically positive increase in structural aberrations at 4 and 20-h exposure without S9 and also at 4-h exposure with S9. The in vivo micronucleus assay also revealed a statistically positive response for micronucleus formation at 500, 100 and 10 mg/kg at 24 and 48-h post-dose. Thus, DON appears to be negative in the Ames test but positive in the in vitro chromosome aberration assay and in the in vivo micronucleus assay. In conclusion, the results indicate DON is a genotoxic compound with a plausible epigenetic mechanism.

Original languageEnglish
Pages (from-to)518-527
Number of pages10
JournalToxicology Mechanisms and Methods
Volume27
Issue number7
DOIs
StatePublished - 2 Sep 2017

Fingerprint

Diazooxonorleucine
Norleucine
Toxicity
Assays
Aberrations
Chromosomes
Chromosome Aberrations
Micronucleus Tests
Salmonella
Salmonella typhimurium
Cricetulus
Glutamine
Epigenomics
Bone Marrow Cells
Escherichia coli
Antiviral Agents
Analgesics
Ovary
Bone
Erythrocytes

Keywords

  • 6-Diazo-5-oxo-l-norleucine (DON)
  • Ames
  • chromosomal aberrations
  • micronucleus

Cite this

Kulkarni, Rohan M. ; Dakoulas, Emily W. ; Miller, Kenneth ; Terse, Pramod S. / Evaluation of genetic toxicity of 6-diazo-5-oxo-l-norleucine (DON). In: Toxicology Mechanisms and Methods. 2017 ; Vol. 27, No. 7. pp. 518-527.
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Evaluation of genetic toxicity of 6-diazo-5-oxo-l-norleucine (DON). / Kulkarni, Rohan M.; Dakoulas, Emily W.; Miller, Kenneth; Terse, Pramod S.

In: Toxicology Mechanisms and Methods, Vol. 27, No. 7, 02.09.2017, p. 518-527.

Research output: Contribution to journalArticle

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AU - Kulkarni, Rohan M.

AU - Dakoulas, Emily W.

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