Enhancement of pancreatic and hepatic glutathione levels in rats during cyanohydroxybutene intoxication

Abstract

1-Cyano-2-hydroxy-3-butene (CHB), a cruciferous plant product, is hepatotoxic, pancreatotoxic, and elevates glutathione (GSH) in liver and pancreas. Whether GSH elevation is preceded by a depletion related to toxic insult, or whether toxicity and GSH elevation are unrelated, is not known. To evaluate the temporal relationship between toxicity and GSH levels, male Fisher 344 rats (6/group) were given CHB (200 mg/kg po) and killed up to 96 hr after dosing. At death, histological and ultrastructural evaluations and GSH GSSG determinations were performed on liver and pancreas. In pancreas, dilatation of the cisternae of the rough endoplasmic reticulum (RER) was evident from 2 hr, becoming progressively more severe 4 and 6 hr after CHB. Frank apoptosis and loss of zymogen granules was evident by 6 hr, becoming widespread by 12 hr. Recovery had commenced by 72 hr, and 50% of treated rats had normal pancreata by 96 hr. No hepatic lesions were observed at this dose. Pancreatic GSH was depressed below 20% at 2 and 4 hr, rose to a maximum of 540% by 12 hr, and remained elevated in treated rats throughout the study (275% at 96 hr). Hepatic GSH only fell to 50%, rose to 150–180%, and returned to normal by 96 hr. While this pattern of depletion and rebound following exposure to hepatotoxins is common, the exaggerated and persistent elevation of pancreatic GSH is unprecedented.