Modulation of diethylnitrosarnine-initiated placental glutathione S-transferase positive preneoplastic and neoplastic lesions by clofibrate, a hepatic peroxisome proliferator

Abstract

The effect of clofibrate (CF) on proliferation of diethylnitrosamine (DEN)-initiated glutathione S-transferase placental form (GST-P)-positive preneoplastic and neoplastic lesions as studied in male F344 rats. Animals were given a single i.p. injection of 200 mg/kg body weight of DEN, and then from 2 weeks later were given a diet containing 0.3% CF (group 1), or no supplement (group 2) until week 64. Group 3 received an injection of 0.9% NaCl instead of DEN and then a diet containing 0.3% CF, like group 1. Animals in all groups were subjected to partial hepatectomy at week 3 and killed at weeks 8, 20, 32, 49 or 64. The results showed that development of GST-P-positive lesions was significantly less in group 1 than in group 2 from week 8 (P less than 0.05). However, in group 1, morphologically distinguishable GST-P-negative preneoplastic lesions increased from week 20 (P less than 0.05), and the total number of GST-P-positive and -negative lesions was significantly greater than that in group 2 from week 32 (P less than 0.05). The induction of hepatocellular carcinoma (HCC) was greater in group 1 than in group 2 from week 49. All the HCCs induced in group 2 were GST-P-positive, whereas 38.9% (7/18) of those in group 1 were GST-P-negative. In group 3, only a few GST-P-positive and/or -negative preneoplastic lesions developed by week 64. These results suggest that CF has tumor-promoting activity, and that GST-P-positive cells induced by DEN changed to GST-P-negative cells on subsequent treatment with CF.

Modifying Effects of Chemicals on the Development of Liver Preneoplastic Placental Glutathione S-Transferase Positive Foci in Analbuminemic and Sprague-Dawley Rats

“…27), hepatocarcinomas induced by peroxisome proliferators such as clofibrate are preceded by foci lesions, as indicated by routine hematoxylin and eosin, adenosine triphosphatase, or glucose-6-phosphatase procedures but are mostly negative under (immuno)histochemical GGT and GST-P stainings (5,8,10). Clofibrate possibly alters the phenotypic expression of GST-P+ foci, turning them GST-P- (10). This is in line with observations of the absence of GGT, GST-P, and a-fetoprotein messenger RNAs in liver tumors induced by peroxisome proliferators (29) and is ultimately expressed by diminished values for number and area ofGST-P+ foci under clofibrate treatment.…”

An overview of peroxisome proliferator-induced hepatocarcinogenesis.

“…The failure of y-glutamyl transpeptidase expression is irreversible and cannot be altered by the administration of genotoxic carcinogens (43). Similar enzyme patterns are also reported in lesions initiated by diethylnitrosamine and promoted by peroxisome proliferators (35,37). In addition, HCC are low in the activities of drug metabolizing and detoxifying enzymes and epoxide hydrolase (44).…”

“…The original description of the carcinogenic effect of nafenopin in mice by Reddy et al in 1976 (30) was followed by several reports establishing several peroxisome proliferators as complete hepatocarcinogens in rats and mice (7,20,(31)(32)(33)(34)(35)(36)(37)(38). Chronic administration of peroxisome proliferators results in the appearance of liver lesions in a sequential fashion.…”

Inhibitory effects of KAT-681, a liver-selective thyromimetic, on development of hepatocellular proliferative lesions in rats induced by 2-acetylaminofluorene and partial hepatectomy after diethylnitrosamine initiation

“…Therefore, inhibition of the expression of these enzymes by KAT suggests antitumorigenic effects on development of hepatocellular tumors. Peroxisome proliferators (PPs) and retinoids are known to be agents that can reduce carcinogen-induced preneoplastic lesions identified by GST-P-and GGTstaining in the liver (Bana et al 1991;Chen et al 1994;Hosokawa et al 1989;Moriwaki et al 1988). It is interesting that the receptors of thyroid hormones belong to the same superfamily of nuclear receptors as those of PPs and retinoids (Kumar and Thompson 1999).…”