MECHANISMS FOR THE PANCREATIC ONCOGENIC EFFECTS OF THE PEROXISOME PROLIFERATOR WYETH-14,643

Several peroxisome proliferators have been shown to produce pancreatic acinar cell hyperplasia/adenocarcinomas in 2-year bioassays with rats : ammonium perfluorooctanoate (C8), clofibrate, methylclofenapate, HCF C-123, and Wyeth-14,643 (WY). We have used in vitro (C8, WY) and in vi vo (WY) approaches to examine several possible mechanisms of pancreati c tumorigenesis by peroxisome proliferating compounds. These mechanism s include cholecystokinin receptor agonism (CCKA), trypsin inhibition, alterations in gut fat content, cholestasis, and altered bile flow/co mposition. All of these mechanisms enhance pancreatic growth either by binding to the CCKA receptor or by increasing plasma CCK levels. In v itro experiments using a receptor competition binding assay demonstrat ed that WY and C8 do not bind directly to the CCKA receptor. In a cont inuous spectrophotometric assay, WY and C8 also failed to inhibit tryp sin, a common mechanism for increasing plasma CCK levels. These in vit ro results suggested that WY was not acting via the two most common me chanisms for modulation of pancreas growth. Two types of in vivo exper iments were conducted. The subchronic study (2-month duration) was des igned primarily to detect early changes in pancreatic growth such as t hose mediated by compounds that inhibit trypsin or act as CCKA recepto r agonists. The chronic study (6 months) was designed primarily to eva luate whether the pancreatic lesions were secondary to hepatic changes such as cholestasis and/or altered bile flow/composition. In the in v ivo experiments, male Crl:CDBR rats were fed diets containing 0 or 100 ppm WY. In the subchronic study WY-treated rats had a twofold increas e in mean relative liver weights, an eightfold increase in hepatic per oxisomal proliferation, and a fourfold increase in hepatocyte cell pro liferation after 1 week which remained elevated throughout the 2 month s of treatment. In contrast, no pancreatic weight effects, increases i n plasma CCK, or acinar cell proliferation was seen through 2 months i n the WY group when compared to the control group. Fecal fat concentra tions were also measured at 2 months and demonstrated no difference be tween control and WY-treated animals. The absence of any early pancrea s changes in the subchronic study is consistent with the in vitro data which demonstrated that WY is not a CCKA agonist or a trypsin inhibit or. The chronic study demonstrated increases in pancreatic weights at 3 months (6% above control) and 6 months (17% above control), as well as increased CCK plasma levels in the WY-treated group. Liver effects in the chronic study paralleled those of the subchronic time points. C linical pathology endpoints including increased serum concentrations o f bile acids, alkaline phosphatase, and bilirubin were indicative of c holestasis in the chronic WY-treated group. The cholestasis may be res ponsible for the downward trend in total bile acid output, both of whi ch may contribute to the modest increases in plasma CCK levels. These results indicate that chronic exposure to WY causes liver alterations such as cholestasis, which may increase plasma concentrations of CCK. Hence, WY may induce pancreatic acinar cell adenomas/adenocarcinomas v ia a mild but sustained increase in CCK levels secondary to hepatic ch olestasis. (C) 1997 Academic Press.