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 journalArticlepeer-review

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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