DIFFERENCES BETWEEN THE PROMOTING ACTIVITIES OF THE PEROXISOME PROLIFERATOR WY-14,643 AND PHENOBARBITAL IN RAT-LIVER

  • 15 June 1989
    • journal article
    • research article
    • Vol. 49  (12) , 3246-3251
Abstract
In order to characterize the promoting activity of the peroxisome proliferator [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14463), male f344 rats which received a single 150-mg/kg dose of diethylnitrosamine (DEN) were fed 0.1% wY-14643 or 0.05% phenobarbital in the diet for 11, 22, or 54 wk. WY-14643 promoted the development of ATPase-deficient foci but not GGTase-positive or G6Pase-deficient foci, in contrast to phenobarbital which promoted development of foci detected by all three markers. The mode of promotion of ATPase-deficient foci by WY-14643 was distinctly different from that of phenobarbital.WY-14643 primarily increased mean volume of foci at 11 and 22 wk, while phenobarbital primarily increased the numerical density of foci at these time points. At 54 wk, the yield of hepatic neoplasms per liver was higher in rats fed WY-14643 than in rats fed phenobarbital. To evaluate the possibility that the promotional activity of WY-14643 was more effective at a later stage in hepatocarcinogenesis, rats receiving a dose of DEN and then phenobarbital in the diet for 11 wk were changed to a diet containing WY-14643 for an additional 11 or 43 wk. However, WY-14643 feeding from wk 11 to 22 caused a reduction in volume density of ATPase-deficient foci relative to the volume density of foci at 11 wk. In addition, feeding WY-14643 from wk 11 to 54 caused similar yields of hepatic neoplasms whether or not phenobarbital was fed for the initial 11 wk. WY-14643 induced hepatic peroxisome proliferation as indicated by palmitoyl CoA oxidase activity regardless of prior treatment with DEN and/or phenobarbital. The yield of neoplasms in rats not receiving DEN was greater in rats fed WY-14643 for wk 11 to 54 than in rats fed WY-14643 for wk 1 to 54. In summary, the peroxisome proliferator WY-14643 was a more efficient promoter of hepatocarcinogenesis in DEN-initiated rats than phenobarbital. The promotional activity of WY-14643, when evaluated by stereological analysis and by changing promoters, is distinct from that of phenobarbital, perhaps suggesting different cellular and/or molecular mechanisms of promotion. Understanding the role of promotion by WY-14643 and other peroxisome proliferators may be important in understanding the mechanism of their hepatocarcinogenicity.

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