Studies on the mechanism of haloacetonitrile-induced gastrointestinal toxicity: interaction of dibromoacetonitrile with glutathione and glutathione-S-transferase in rats.
The haloacetonitrile, dibromoacetonitrile (DBAN), is a direct-acting genotoxic agent that has been detected in drinking water. In a time course study, male Sprague-Dawley rats were treated with DBAN (75 mg/kg PO), and killed at 0.5, 1, 2, and 4 hr after treatment. In a dose response study, animals were treated orally with various doses of DBAN (25, 50, 75, and 100 mg/kg) and killed at one-half hour after treatment. Control animals received 1 ml/kg PO of the vehicle dimethyl sulfoxide (DMSO). In both experiments blood and organs were collected and stored at -80 degrees C until the time of analysis. At 0.5 hr after treatment, a single oral dose of DBAN caused a significant decrease of glutathione (GSH) concentrations in liver (54% of control) and stomach (6% of control). Hepatic GSH depletion was maximal at 0.5 hr and rebound to the control levels by 4 hr. In contrast, gastric GSH concentrations remained low at all time points. DBAN caused an insignificant change in both kidney and blood GSH levels. DBAN significantly inhibited glutathione-S-transferase (GST) activity in liver and stomach. Hepatic GST inhibition was maximal (34% of control) at 2 hr and minimal (80% of control) at 4 hr. Meanwhile, in the stomach GST activity was inhibited at 1 hr (60% of control) and remained low at all times after treatment. Both GSH depletion and GST inhibition were dose-dependent. This study indicates that GSH and GST play an important role in the metabolism and detoxification of DBAN in rats. The prolonged depletion of GSH and inhibition of GST in the gastrointestinal (GI) tissues suggest that the GI tract is a major target for DBAN toxicity.
Department of Pathology, University of Texas Medical Branch, Galveston 77550.
A E
AE
Ahmed
G I
GI
Hussein
J P
JP
Loh
S Z
SZ
Abdel-Rahman
D000097:Acetonitriles / Q000633:toxicity*; D000818:Animals; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000378:metabolism; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000473:pathology; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains; D013270:Stomach / Q000187:drug effects
D000097:Acetonitriles; D005982:Glutathione Transferase; D005978:Glutathione; C051715:dibromoacetonitrile