Contrasting hepatocytic peroxisome proliferation, lipofuscin accumulation and cell turnover for the hepatocarcinogens Wy-14,643 and clofibric acid.
Earlier studies indicated that the hepatocarcinogenic activity of two peroxisome proliferators (PP) Wy-14,643 and di(2-ethylhexyl)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 (approximately 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 greater than WYLD approximately equal to CA greater than 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 40-fold over controls respectively) while CA induced a 10-fold response over controls (control LI less than or equal to 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.
Marsman
D S
DS
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Goldsworthy
T L
TL
Popp
J A
JA
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division; D002995:Clofibric Acid / Q000633:toxicity*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004435:Eating / Q000187:drug effects; D008062:Lipofuscin / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D004273:DNA, Neoplasm; D008062:Lipofuscin; D011743:Pyrimidines; D002995:Clofibric Acid; C006253:pirinixic acid