Mechanisms for the Pancreatic Oncogenic Effects of the Peroxisome Proliferator Wyeth-14,643

Abstract

Several peroxisome proliferators have been shown to produce pancreatic acinar cell hyperplasia/adenocarcinomas in 2-year bioassays with rats: ammonium perfluorooctanoate (C8), clofibrate, methylclofenapate, HCFC-123, and Wyeth-14,643 (WY). We have usedin vitro(C8, WY) andin vivo(WY) approaches to examine several possible mechanisms of pancreatic tumorigenesis by peroxisome proliferating compounds. These mechanisms include cholecystokinin receptor agonism (CCKA), trypsin inhibition, alterations in gut fat content, cholestasis, and altered bile flow/composition. All of these mechanisms enhance pancreatic growth either by binding to the CCKAreceptor or by increasing plasma CCK levels.In vitroexperiments using a receptor competition binding assay demonstrated that WY and C8 do not bind directly to the CCKAreceptor. In a continuous spectrophotometric assay, WY and C8 also failed to inhibit trypsin, a common mechanism for increasing plasma CCK levels. Thesein vitroresults suggested that WY was not acting via the two most common mechanisms for modulation of pancreas growth. Two types ofin vivoexperiments were conducted. The subchronic study (2-month duration) was designed primarily to detect early changes in pancreatic growth such as those mediated by compounds that inhibit trypsin or act as CCKAreceptor agonists. The chronic study (6 months) was designed primarily to evaluate whether the pancreatic lesions were secondary to hepatic changes such as cholestasis and/or altered bile flow/composition. In thein vivoexperiments, male Crl:CDBR rats were fed diets containing 0 or 100 ppm WY. In the subchronic study WY-treated rats had a twofold increase in mean relative liver weights, an eightfold increase in hepatic peroxisomal proliferation, and a fourfold increase in hepatocyte cell proliferation after 1 week which remained elevated throughout the 2 months of treatment. In contrast, no pancreatic weight effects, increases in plasma CCK, or acinar cell proliferation was seen through 2 months in the WY group when compared to the control group. Fecal fat concentrations were also measured at 2 months and demonstrated no difference between control and WY-treated animals. The absence of any early pancreas changes in the subchronic study is consistent with thein vitrodata which demonstrated that WY is not a CCKAagonist or a trypsin inhibitor. 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. Clinical pathology endpoints including increased serum concentrations of bile acids, alkaline phosphatase, and bilirubin were indicative of cholestasis in the chronic WY-treated group. The cholestasis may be responsible for the downward trend in total bile acid output, both of which 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 via a mild but sustained increase in CCK levels secondary to hepatic cholestasis.