Hepatocellular DNA synthesis in rats given peroxisome proliferating agents: comparison of WY-14,643 to clofibric acid, nafenopin and LY171883.
The mitogenic effects of peroxisome proliferating agents have been implicated in their carcinogenicity. WY-14,643 stimulates an increase in hepatocellular DNA replication that persists with continued administration, but it is unclear if other peroxisome proliferators share this property. In these studies, WY-14,643 was compared to clofibric acid, nafenopin and LY171883 given to rats in the diet for up to 30 days. DNA replication in the rat liver was quantified by immunohistochemical methods after continuous s.c. infusion of bromodeoxyuridine by osmotic minipump. During the first 7 days of treatment, WY-14,643 (0.1% in diet) and nafenopin (0.05%) increased the percentage of bromodeoxyuridine-labeled hepatocytes to greater than 50%, from 3% in controls. Clofibric acid (0.5%) and LY171883 (0.3%) increased the labeling to approximately 33%. The replicative response to each of the compounds was localized primarily to the periportal region of the liver lobule. The time-course of replication induced by clofibric acid and WY-14,64.3 was examined over 3 day intervals. The peak of replication in response to clofibric acid occurred during days 4-6, whereas the effect of WY-14,643 peaked during days 1-3 and was much greater than clofibric acid. The replicative response to WY-14,643 persisted through 30 days at dietary concentrations of 0.1 and 0.005%. Nafenopin, LY171883 and clofibric acid were without effect on DNA replication on days 28-30 even though the hepatomegaly and induction of peroxisomal beta-oxidation persisted. Thus, under the conditions of these experiments, the persistent replicative effect through 30 days was unique to WY-14,643. Although sustained replication in the general population of hepatocytes may be involved in the carcinogenesis of WY-14,643, it does not appear to be a factor in the hepatocarcinogenesis of the other peroxisome proliferators.
Eacho
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Toxicology Division, Eli Lilly Company, Greenfield, IN 46140.
Lanier
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Brodhecker
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D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001973:Bromodeoxyuridine; D002995:Clofibric Acid / Q000494:pharmacology*; D004261:DNA Replication; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000378:metabolism; D009255:Nafenopin / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013777:Tetrazoles / Q000494:pharmacology*
D000098:Acetophenones; D011743:Pyrimidines; D013777:Tetrazoles; D009255:Nafenopin; D002995:Clofibric Acid; C006253:pirinixic acid; C044660:LY 171883; D001973:Bromodeoxyuridine