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Contrasting hepatocytic peroxisome proliferation, lipofuscin accumulation and cell turnover for the hepatocarcinogens Wy-14,643 and clofibric acid
Chemical Industry Institute of Toxicology, Six Davis Drive, P0 Box 12137, Research Triangle Park NC 27709, USA
1To whom correspondence should be addressed
Earlier studies indicated that the hepatocarcinogenic activity of two peroxisome proliferators (PP) Wy-14,643 and di(2-ethythexyl)phthalate (DEHP) correlated to the degree of lipofuscin accumulation and sustained cell replication rather than the level of peroxisome induction. This study extends the comparison of peroxisome proliferation, lipofuscin accumulation and cell replication responses in rats fed (i) clofibric acid at 5000 p.p.m. (CA), a regimen of moderate hepatocarcinogenicity; (ii) Wy-14,643 at 50 p.p.m. (WYLD), a dose of unknown hepatocarcinogenicity; and (iii) Wy-14,643 at 1000 p.p.m. (WYHD), as the highly hepatocarcinogenic regimen. Adult male F344 rats were fed the experimental diets for 1, 2, 5, 11 or 22 weeks. Relative liver weights (% of body weight) were increased in rats fed CA (1.6- to 1.7-fold), WYHD or WYLD (2.0- to 2.7-fold), compared to controls (
3%) at all time points. All rats fed CA, WYHD or WYLD had similar hepatic peroxisome proliferation at all time points with large elevations in peroxisomal enzyme activities and number, size and mean volume of peroxisomes. In contrast, hepatocytic lipofuscin accumulation differed between treatments, with a decreasing order of accumulation observed in WYHD > WYLD 
CA > controls. Replicative DNA synthesis (as assessed by nuclear labeling index, LI) in nonlesion hepatocytes was markedly elevated at 1 week by both WYHD and WYLD (45- and 44-fold over controls respectively) white CA induced a 10-fold response over controls (control LI 
1%). From week 2 to week 22 the hepatocytic LI was sustained in WYHD and WYLD rats (8- and 4-fold over controls respectively) but not in CA-rats, as compared to controls. In contrast to the cell replication response, apoptosis was elevated only in WYHD at 22 weeks. Collectively, this study supports the conclusion that neither hepatomegaly nor peroxisome proliferation are accurate predictors of carcinogenic activity for PP. Further, these results suggest that if lipofuscin accumulation or sustained cell turnover are indicators of PP-induced carcinogenesis, then WYLD should be at least as carcinogenic as CA. The moderate carcinogenic activity of CA also suggests that additional factor(s) may be necessary besides lipofuscin accumulation and sustained cell replication to determine the ultimate carcinogenic activity of PP.
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