Lack of peroxisomal enzyme inducibility in rat hepatic preneoplastic lesions induced by mutagenic carcinogens: contrasted expression of glutathione S-transferase P form and enoyl CoA hydratase.
While glutathione S-transferase P form (GST-P), a reliable marker for preneoplastic lesions induced by mutagenic hepatocarcinogens, is generally not expressed in rat liver foci, hyperplastic nodules and hepatomas induced by peroxisome proliferators (PPs), such lesions can be detected due to their peroxisomal enzyme-negative nature. For comparative purposes we examined the inducibility of enoyl CoA hydratase (ECH), a key peroxisomal enzyme, in rat hepatic preneoplastic lesions induced by mutagenic carcinogens. Clofibrate (CF) was therefore administered for 2 or 4 weeks following performance of the Solt-Farber protocol using diethylnitrosamine and 2-acetylaminofluorene. Immunohistochemical examination revealed no or only very weak expression of ECH within the induced foci in clear contrast to the strong staining of surrounding parenchyma. ECH expression was thus diametrically opposed to that of GST-P which was found only in foci. Although ECH was completely lacking in GST-P-strongly positive foci, it was expressed in GST-P-negative hepatocytes inside some foci otherwise positive for GST-P. CF administration resulted in a significant decrease in the numbers and areas of foci exhibiting strongly positive or positive GST-P staining; this being reflected in a lowering of GST-P protein levels. Furthermore, in primary cultured rat hepatocytes, clofibric acid as well as dexamethasone suppressed the expression of both GST-P and the oncogene, c-jun. These results taken together suggest that possible interaction of the PP receptor with JUN might be involved in loss of ECH expression in GST-P-strongly positive foci.
Yokoyama
Y
Y
Second Department of Biochemistry, Hirosaki University School of Medicine, Japan.
Tsuchida
S
S
Hatayama
I
I
Sato
K
K
D000818:Animals; D002478:Cells, Cultured; D002994:Clofibrate / Q000633:toxicity; D002995:Clofibric Acid / Q000633:toxicity; D003907:Dexamethasone / Q000494:pharmacology; D004746:Enoyl-CoA Hydratase / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D016758:Genes, jun; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D008830:Microbodies / Q000201:enzymology*; D009153:Mutagens / Q000633:toxicity*; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D009153:Mutagens; D012333:RNA, Messenger; D002995:Clofibric Acid; D003907:Dexamethasone; D005982:Glutathione Transferase; D004746:Enoyl-CoA Hydratase; D002994:Clofibrate