Induction of altered hepatic foci in rats by the administration of hypolipidemic peroxisome proliferators alone or following a single dose of diethylnitrosamine.
The effect of feeding hypolipidemic peroxisome proliferators on the induction of altered hepatic foci (AHF) in Fischer rats was studied in order to determine whether such agents can induce or promote the development of AHF. In the first study, rats were fed ciprofibrate (10 mg/kg/day) for 1 yr. AHF, neoplastic nodules, and hepatocellular carcinomas were induced. The presence of putative gamma-glutamyltranspeptidase (GGT) activity was numerically the most common marker, although it was absent in larger foci and nodules. A deficiency in canalicular ATPase and glucose-6-phosphatase provided the best markers for the larger foci and nodules. In the second study, rats were subjected to partial hepatectomy, and half of the animals were then intubated with diethylnitrosamine (10 mg/kg). One wk later, rats were fed Wy-14,643 at concentrations of 0, 0.05, and 0.1% in the diet for 6 mo. At 6 mo, the number and volume of foci were increased by the feeding of Wy-14,643 after partial hepatectomy alone and were greatly increased when Wy-14,643 was fed after partial hepatectomy/diethylnitrosamine administration. Canalicular adenosine triphosphatase and glucose-6-phosphatase deficiencies were the most common markers of AHF, and AHF of these phenotypes occupied practically all of the focal volume. The larger AHF did not express GGT, and those foci exhibiting GGT were much less common and occupied very little volume. The absence of the GGT protein itself, as opposed to an inhibition of GGT activity, was verified by immunohistochemical staining using an antibody to GGT. These studies show that hypolipidemic peroxisome proliferators can stimulate an increase in AHF following a single dose of diethylnitrosamine and a mitotic stimulus, and they thus can act as promoters in two-stage liver carcinogenesis. GGT is a poor marker for identifying AHF induced by peroxisome proliferators during the early, premalignant phase of hepatocarcinogenesis.
Glauert
H P
HP
Beer
D
D
Rao
M S
MS
Schwarz
M
M
Xu
Y D
YD
Goldsworthy
T L
TL
Coloma
J
J
Pitot
H C
HC
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002994:Clofibrate / Q000031:analogs & derivatives*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004052:Diethylnitrosamine; D004334:Drug Administration Schedule; D058607:Fibric Acids; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006498:Hepatectomy; D007158:Immunologic Techniques; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008830:Microbodies / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D058607:Fibric Acids; D011743:Pyrimidines; D004052:Diethylnitrosamine; D002995:Clofibric Acid; C006253:pirinixic acid; D005723:gamma-Glutamyltransferase; D005952:Glucose-6-Phosphatase; D000251:Adenosine Triphosphatases; C019304:ciprofibrate; D002994:Clofibrate