Decreased connexin32 and a characteristic enzyme phenotype in clofibrate-induced preneoplastic lesions not shared with spontaneously occurring lesions in the rat liver.
Two different types of focal preneoplastic lesions, tentatively named Type I and II lesions, were recognized in the liver of rats chronically treated with clofibrate for 104 weeks. Type I lesions were characterized by mostly negative glucose-6-phosphate dehydrogenase (G6PD) activity (6 out of 10, 60%) and positive expression of succinate dehydrogenase (10 out of 10, 100%), in addition to the previously documented complete lack of expression of glutathione S-transferase, placental form (GST-P) and gamma-glutamyl transpeptidase (GGT). Furthermore, most importantly, Type I lesions exhibited a clear decrease in immunohistochemically demonstrated connexin32 (Cx32) spot counts on their hepatocyte membranes, similarly to nitrosamine-induced lesions. In contrast, Type II lesions, mostly small in size and positively expressing GST-P and/or GGT and G6PD, similarly to their previously reported nitrosamine-induced counterparts, did not exhibit a significant decrease in Cx32 count. In addition, spontaneously occurring lesions, again sharing the same enzyme phenotype, did not show a decrease in Cx32. The results indicate that: (i) a clear distinction between the two lesions, with Type I being involved in clofibrate-induced tumors and Type II being more likely to be spontaneous in nature; (ii) a decrease in Cx32 is closely linked to lesion development and possibly stage of progression, irrespective of the enzyme phenotype and the applied carcinogen; (iii) the unaltered condition of Cx32 may suggest a slow growing or non-progressive nature.
Tsuda
H
H
Chemotherapy Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Asamoto
M
M
Iwahori
Y
Y
Hori
T
T
Ota
T
T
Baba-Toriyama
H
H
Uehara
N
N
Kim
D J
DJ
Krutovskikh
V A
VA
Takasuka
N
N
Tsuchiya
T
T
Mutai
M
M
Tatematsu
M
M
Yamasaki
H
H
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002994:Clofibrate / Q000633:toxicity*; D017630:Connexins / Q000378:metabolism*; D004052:Diethylnitrosamine / Q000031:analogs & derivatives / Q000633:toxicity; D005982:Glutathione Transferase / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects; D010641:Phenotype; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D005723:gamma-Glutamyltransferase / Q000378:metabolism; D000097002:Gap Junction beta-1 Protein
D002273:Carcinogens; D002994:Clofibrate; D017630:Connexins; D004052:Diethylnitrosamine; D005982:Glutathione Transferase; D005723:gamma-Glutamyltransferase; D000097002:Gap Junction beta-1 Protein; C023845:N-ethyl-N-hydroxyethylnitrosamine