In order to characterize the promoting activity of the peroxisome proliferator [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]
acetic acid (WY-14,463), male F344 rats which received a single 150-mg/kg dose of
diethylnitrosamine (DEN) were fed 0.1%
WY-14,643 or 0.05%
phenobarbital in the diet for 11, 22, or 54 wk.
WY-14,643 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-14,643 was distinctly different from that of
phenobarbital.
WY-14,643 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-14,643 than in rats fed
phenobarbital. To evaluate the possibility that the promotional activity of
WY-14,643 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-14,643 for an additional 11 or 43 wk. However,
WY-14,643 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-14,643 from wk 11 to 54 caused similar yields of
hepatic neoplasms whether or not
phenobarbital was fed for the initial 11 wk.
WY-14,643 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-14,643 for wk 11 to 54 than in rats fed
WY-14,643 for wk 1 to 54. In summary, the peroxisome proliferator
WY-14,643 was a more efficient promoter of hepatocarcinogenesis in DEN-initiated rats than
phenobarbital. The promotional activity of
WY-14,643, 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-14,643 and other
peroxisome proliferators may be important in understanding the mechanism of their hepatocarcinogenicity.