4 Hydroxyaminoquinoline 1 oxide induced pancreatic necrosis and regeneration in the guinea pig: ultrastructural and autoradiographic studies

4 Hydroxyaminoquinoline 1 oxide (4 HAQO), a potent mutagen and carcinogen, caused selective necrosis of exocrine pancreas in inbred strain 13 guinea pigs when injected i.v. in a single dose (15 to 22.5 mg/kg body weight). Necrosis of acinar cells of pancreas was evident as early as 18 hr after a single injection of 4 HAQO. By light microscopy, the maximum necrotic changes were noted by 48 to 56 hr, as evidenced by the distortion of acinar and lobular architecture of the pancreas. These changes were associated with a marked elevation of serum amylase concentration and concomitant reduction in amylase activity in the pancreatic tissue. Ultrastructural studies of pancreas between 18 and 36 hr after 4 HAQO injection revealed segregation of acinar cell nucleolus into granular and fibrillar components, marked dilation of rough endoplasmic reticulum, disaggregation of ribosomes and progressive depletion of zymogen granules. By 48 hr, several pancreatic acinar cells contained complex myelin figures and areas of focal cytoplasmic degradation. After the necrotic phase, the surviving guinea pigs showed a significant regeneration of pancreatic acinar tissue. Numerous mitoses were encountered between 60 to 72 hr after 4 HAQO administration. Similarly, ³H thymidine autoradiographic studies indicated a striking increase in the labeling index of acinar cell nuclei that reached peak value by 66 hr. These dividing cells appeared to participate in repair of partially damaged acini and also in the formation of new acini. The acinar cell repair, as well as the formation of new acini in many pancreatic lobules, was complete by 84 to 96 hr, as indicated by light and electron microscopic findings and the recovery of pancreatic tissue amylase levels. These studies demonstrate that a single i.v. injection of 4 HAQO causes a profound necrosis of the exocrine pancreas in guinea pigs which is followed by a significant degree of regeneration.