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

Abstract

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).(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: N Wada, D S Marsman, J A Popp
• Journal: Fundamental and applied toxicology : official journal of the Society of Toxicology (Fundam Appl Toxicol) Vol. 18 Issue 1 Pg. 149-54 (Jan 1992) ISSN: 0272-0590 [Print] United States
• PMID: 1601204 (Publication Type: Journal Article)

Chemical References

• Carcinogens
• Lipofuscin
• Pyrimidines
• Palmitoyl Coenzyme A
• pirinixic acid
• DNA
• Carnitine O-Acetyltransferase
• Thymidine

Topics

• Animals
• Autoradiography
• Body Weight (drug effects)
• Carcinogens (toxicity)
• Carnitine O-Acetyltransferase (metabolism)
• Cell Division (drug effects)
• Chemical and Drug Induced Liver Injury (enzymology, metabolism)
• DNA (biosynthesis)
• Dose-Response Relationship, Drug
• Lipofuscin (pharmacokinetics)
• Liver (cytology, drug effects)
• Male
• Microbodies (drug effects)
• Organ Size (drug effects)
• Palmitoyl Coenzyme A (metabolism)
• Paraffin Embedding
• Pyrimidines (toxicity)
• Rats
• Rats, Inbred F344
• Thymidine (metabolism)