Role of glutathione modulation in acrylonitrile-induced gastric DNA damage in rats

Ahmed E. Ahmed, Amr M. Nouraldeen, Sherif Z. Abdel-Rahman, Srinivasan Rajaraman

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Acrylonitrile (VCN) or its reactive metabolites irreversibly interact with gastric DNA in vivo and cause DNA damage. The effect of glutathione (GSH) modulation on VCN-induced genotoxicity and unscheduled DNA repair synthesis (UDRS) in DNA of gastric mucosal tissues was investigated. VCN-induced UDRS was determined: in control rats, rats with depleted gastric GSH contents, and rats treated with sulfhydryl compounds. A single oral dose (23 mg/kg) of VCN induced a time- and dose-dependent increase in gastric UDRS and decrease in GSH levels. While maximal UDRS in gastric mucosa was observed 2 h following oral administration of 23 mg/kg VCN, maximal GSH depletion (50% of control) was detected 4 h following treatment. Increasing the VCN dose to 46 mg/kg caused a further decrease in gastric GSH level (27% of control), while UDRS was elevated. Inhibition of VCN oxidation by treatment of the animals with the cytochrome P450 inhibitor, SKF 525-A, prior to VCN administration caused 65% reduction in VCN-induced UDRS. Treatment of rats with the GSH depletor diethylmaleate (DEM) prior to VCN administration caused 167% increase in UDRS in gastric mucosal tissues. Treatment of the animals with the sulfhydryl compounds, cysteine and penicillamine, prior to VCN administration protected against VCN-induced UDRS. The results demonstrated an inverse and highly significant correlation between gastric GSH levels and VCN-induced UDRS (r = - 0.873, P < 0.0001). In conclusion, our study indicates that VCN bioactivation and the homeostasis of gastric GSH may play a major role in the initial processes underlying VCN-induced gastric carcinogenesis.

Original languageEnglish (US)
Pages (from-to)620-627
Number of pages8
JournalArchives of Toxicology
Volume70
Issue number10
DOIs
StatePublished - Aug 20 1996

Keywords

  • Acrylonitrile
  • DNA damage
  • Diethylmaleate
  • Glutathione
  • Unscheduled DNA repair synthesis

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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