Dose-related effects of the hepatocarcinogen, Wy-14,643, on peroxisomes and cell replication

• Published in: Fundamental and applied toxicology Vol. 18; no. 1; pp. 149 - 154
• Main Authors: Wada, Naoto, Marsman, Daniel S., Popp, James A.
• Format: Journal Article
• Language: English
• Published: Boston, MA Elsevier Science (USA) 1992; San Diego, CA Academic Press; New York, NY
• Subjects: Animals; Autoradiography; Biological and medical sciences; Body Weight - drug effects; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - toxicity; Carnitine O-Acetyltransferase - metabolism; Cell Division - drug effects; Chemical agents; Chemical and Drug Induced Liver Injury - enzymology; Chemical and Drug Induced Liver Injury - metabolism; DNA - biosynthesis; Dose-Response Relationship, Drug; Lipofuscin - pharmacokinetics; Liver - cytology; Liver - drug effects; Male; Medical sciences; Microbodies - drug effects; Organ Size - drug effects; Palmitoyl Coenzyme A - metabolism; Paraffin Embedding; Pyrimidines - toxicity; Rats; Rats, Inbred F344; Thymidine - metabolism; Tumors; Cell proliferation; Rat; Toxicity; Liver; Rodentia; Time response relation; Peroxisome proliferator; Dose activity relation; Carcinogen; Vertebrata; Mammalia; Investigation method; Animal; Antilipemic agent
• ISSN: 0272-0590; 1095-6832
• DOI: 10.1016/0272-0590(92)90208-Y

The dose and time dependency of peroxisome proliferation and hepatocyte replication was evaluated in the liver of rats fed the peroxisome proliferator and hepatocarcinogen, Wy-14,643. Male F344 rats were fed NIH07 diet blended with Wy-14,643 at 0, 5, 10, 50, 100, or 1000 ppm for 1, 3, 6, or 13 weeks. Hepatomegaly was induced by Wy-14,643 at all doses and at all time points. Peroxisome proliferation was present in rats fed 5 ppm Wy-14,643 as early as 1 week, as determined by the peroxisome-specific NAD + reduction of palmitoyl CoA (PCO) and the peroxisome-associated activity of carnitine acetyltransferase (CAT) (5- and 11-fold over control, respectively). The elevations of PCO and CAT were dose-dependent from 5 to 50 ppm and then plateaued from 50 to 1000 ppm throughout the treatment period. Hepatocellular replication, evaluated by nuclear histoautoradiography ([ 3H]thymidine labeling, 6-day infusion), was increased in all Wy-14,643 dose groups after 1 week of treatment (5 ppm, 4-fold; 10 ppm, 5-fold; 50 ppm, 13-fold; 100 ppm, 12-fold; and 1000 ppm, 13-fold over controls). However, in 5 and 10 ppm groups this cell replication returned to control levels by 3 weeks. In contrast, 50, 100, and 1000 ppm groups had sustained increases in cell replication up to 13 weeks (13 weeks: 6-, 7-, and 9-fold over controls, respectively). We have demonstrated that Wy-14,643 can induce peroxisome proliferation at 5 ppm, a dose 200 times lower than the dose shown to be highly hepatocarcinogenic in rats (100% incidence by 60 weeks). In contrast, 50 ppm was identified as the minimal dose which induced sustained cell replication in rat liver. These data show that peroxisome proliferation can be dissected from sustained cell replication for correlating either peroxisome induction or cell replication with tumor formation. These results provide important information that can be used to design carcinogenicity experiments to test if peroxisome proliferation and/or chronic enhancement of cell replication are predictive risk factors for hepatocarcinogenicity.