Evidence that A8947 enhances pancreas growth via a trypsin inhibitor mechanism.
A8947 is a member of the sulfonyl urea class of compounds and is the active ingredient in a commercial broad leaf herbicide. This compound has been shown to produce pancreatic hypertrophy in rats, mice, and dogs. The objectives of this study were to investigate the mechanism(s) for the A8947 induction of pancreatic acinar cell hypertrophy and proliferation and to evaluate whether these pancreatic changes are reversible. A8947 was fed to male Crl:CD BR rats for up to 28 days (0, 300, 10,000, 30,000 ppm) or 56 days (0, 30,000 ppm). Rats were terminated on Test Days 7, 14, and 28 to assess the time course and dose response for the A8947-induced pancreatic changes, while rats terminated on Test Day 56 were used to assesss the reversibility of the pancreas effects at 30,000 ppm A8947. A8947 produced significant increases in pancreatic weight and acinar cell proliferation and diffuse acinar cell hypertrophy in 7 days at 10,000 and 30,000 ppm dose levels. By Day 14, absolute pancreas weights in the 10,000 and 30,000 ppm groups were maximally increased and remained at these levels throughout the study. In contrast, acinar cell proliferation in the 30,000 ppm group was still elevated at Test Day 14, but attenuated relative to the 7-day response, and returned to control levels by Test Day 28. No effects were observed at 300 ppm after a 28-day exposure period, while complete reversibility of A8947-induced pancreatic effects was demonstrated at 30,000 ppm following a 1-month recovery period (Test Day 56). Cholecystokinin (CCK) levels were increased by A8947 and closely followed the time course for pancreatic changes. MK-329, a specific CCKA receptor antagonist, completely ablated the ability of 30,000 ppm A8947 to increase pancreas weight following 7 days of exposure. A8947 did not bind the CCKA receptor in a receptor competition assay, negating any potential agonist mechanism. A8947 did, however, inhibit trypsin in vitro, suggesting a mechanism of action similar to that of raw soy protein, in which trypsin inhibition in vivo results in increased CCK levels followed by pancreatic acinar cell hypertrophy and proliferation.
Obourn
J D
JD
Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de Nemours & Company, Elkton Road, Newark, Delaware 19714, USA.
Frame
S R
SR
Chiu
T
T
Solomon
T E
TE
Cook
J C
JC
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002766:Cholecystokinin / Q000097:blood; D020109:Devazepide; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000633:toxicity*; D006984:Hypertrophy; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000473:pathology; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000819:agonists; D014361:Trypsin Inhibitors / Q000633:toxicity*
D001570:Benzodiazepinones; D006540:Herbicides; D011743:Pyrimidines; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; D014361:Trypsin Inhibitors; C108349:A 8947; D002766:Cholecystokinin; D020109:Devazepide