Dose-related effects of the hepatocarcinogen, Wy-14,643, on peroxisomes and cell replication.
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)
Wada
N
N
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Marsman
D S
DS
Popp
J A
JA
D000818:Animals; D001345:Autoradiography; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002332:Carnitine O-Acetyltransferase / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D008062:Lipofuscin / Q000493:pharmacokinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008297:Male; D008830:Microbodies / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D016612:Paraffin Embedding; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013936:Thymidine / Q000378:metabolism
D002273:Carcinogens; D008062:Lipofuscin; D011743:Pyrimidines; D010171:Palmitoyl Coenzyme A; C006253:pirinixic acid; D004247:DNA; D002332:Carnitine O-Acetyltransferase; D013936:Thymidine