title: Chloroacetonitrile (CAN) induces glutathione depletion and 8-hydroxylation of guanine bases in rat gastric mucosa.
abstract: Chloroacetonitrile (CAN) is detected in drinking-water supplies as a by-product of the chlorination process. Gastroesophageal tissues are potential target sites of acute and chronic toxicity by haloacetonitriles (HAN). To examine the mechanism of CAN toxicity, we studied its effect on glutathione (GSH) homeostasis and its impact on oxidative DNA damage in gastric mucosal cells of rats. Following a single oral dose (38 or 76 mg/Kg) of CAN, animals were sacrificed at various times (0-24 h), and mucosa from pyloric stomach were collected. The effects of CAN treatment on gastric GSH contents and the integrity of genomic gastric DNA were assessed. Oxidative damage to gastric DNA was evaluated by measuring the levels of 8-Hydroxydeoxyguanosine (8-OHdG) in hydrolyzed DNA by HPLC-EC. The results indicate that CAN induced a significant, dose- and time-dependent, decrease in GSH levels in pyloric stomach mucosa at 2 and 4 hours after treatment (56 and 39% of control, respectively). DNA damage was observed electrophoretically at 6 and 12 hours following CAN administration. CAN (38 mg/Kg) induced significant elevation in levels of 8-OHdG in gastric DNA. Maximum levels of 8-OHdG in gastric DNA were observed at 6 hours after CAN treatment [9.59+/-0.60 (8-OHdG/10(5)dG) 146% of control]. When a high dose of CAN (76 mg/Kg) was used, a peak level of 8-OHdG [11.59+/-1.30 (8-OHdG/10(5)dG) 177% of control] was observed at earlier times (2 h) following treatment. When CAN was incubated with gastric mucosal cells, a concentration-dependent cyanide liberation and significant decrease in cellular ATP levels were detected. These data indicate that a mechanism for CAN-induced toxicity may be partially mediated by depletion of glutathione, release of cyanide, interruption of the energy metabolism, and induction of oxidative stress that leads to oxidative damage to gastric DNA.
authors: Department of Pathology, University of Texas Medical Branch, Galveston 77555-0605, USA. aahmed@utmb.edu
authors: A E
authors: AE
authors: Ahmed
authors: S
authors: S
authors: Jacob
authors: A M
authors: AM
authors: Nouraldeen
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000097:Acetonitriles / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006147:Guanine / Q000378:metabolism*; D006900:Hydroxylation; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000097:Acetonitriles; D006147:Guanine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000255:Adenosine Triphosphate; C069277:chloroacetonitrile; D003849:Deoxyguanosine; D005978:Glutathione