title: Role of glutathione modulation in acrylonitrile-induced gastric DNA damage in rats.
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.
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston 77555-0605, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Ahmed
authors.forename: A M
authors.initials: AM
authors.lastname: Nouraldeen
authors.forename: S Z
authors.initials: SZ
authors.lastname: Abdel-Rahman
authors.forename: S
authors.initials: S
authors.lastname: Rajaraman
mesh_terms: D000181:Acrylonitrile / Q000633:toxicity*; D000818:Animals; D003545:Cysteine / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D010396:Penicillamine / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects*; D013997:Time Factors
chemical_list: D008298:Maleates; D011335:Proadifen; C014476:diethyl maleate; D005978:Glutathione; D010396:Penicillamine; D003545:Cysteine; D000181:Acrylonitrile