Role of glutathione modulation in acrylonitrile-induced gastric DNA damage in rats.
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.
Ahmed
A E
AE
Department of Pathology, University of Texas Medical Branch, Galveston 77555-0605, USA.
Nouraldeen
A M
AM
Abdel-Rahman
S Z
SZ
Rajaraman
S
S
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
D008298:Maleates; D011335:Proadifen; C014476:diethyl maleate; D005978:Glutathione; D010396:Penicillamine; D003545:Cysteine; D000181:Acrylonitrile