Long-term dosing studies using mutagenic carcinogens indicate a highly significant correlation between elevations in the level of rat glutathione S-transferase P messenger RNA and liver tumours of hepatocellular origin.
We have investigated levels of transcript homologous with glutathione S-transferase P (GST-P; GST 7-7) in tumours and hyperplastic lesions induced in the livers of rats by long-term gavage dosing with diethylnitrosamine (DEN) and 6-p-dimethylaminophenylazobenzothiazole (6BT). Detailed histopathological examination of the livers of the 90 animals used in this study at 6-8 months after initiation of daily dosing revealed that, of the 30 animals treated with carcinogen, 15 had developed tumours or hyperplastic lesions. Of these, 11 were areas of fibrosarcoma/fibrous hyperplasia. The remaining four were hepatocellular carcinomas. Northern blotting of total RNA purified from these tissues revealed the presence of transcripts of 3 and 0.75 kb. Evidence is presented to indicate that the former is a hitherto-undetected precursor of the 3-kbp rat GST-P gene, the latter representing the previously characterized mature GST-P transcript. Large elevations of the 0.75-kb transcript (30-35-fold) were encountered in all of the hepatocellular carcinomas, but in none of the other lesions, indicating a highly significant correlation (P = less than 0.001) between high elevations in levels of GST-P mRNA and liver tumours of hepatocellular origin. Minor elevations in transcript level (less than or equal to 5-fold) were encountered in several of the non-hepatocellular lesions. In regenerating livers, small increases in the level of the 3-kb transcript (approximately 3-fold) were routinely detected in total RNA from all partial hepatectomies, a concomitant decrease of approximately similar magnitude occurring in the 0.75-kb transcript, suggesting that minor elevations in levels of GST-P transcript, where encountered in non-hepatocellular lesions, are related to pre-neoplasia rather than to the proliferative rate of hyperplastic cells per se. The data extend previous observations, carried out largely using short-term regimes, to an analysis of transcripts homologous with GST-P in hyperplastic, pre-neoplastic and neoplastic lesions induced by long-term dosing with genotoxic carcinogens, and strongly lend support to the concept that high (30-fold) elevations in GST-P transcript correlate most strikingly with tumours of hepatocellular origin.
D000818:Animals; D052160:Benzothiazoles; D002273:Carcinogens; D004052:Diethylnitrosamine; D004587:Electrophoresis, Agar Gel; D005982:Glutathione Transferase / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009693:Nucleic Acid Hybridization; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles; D014158:Transcription, Genetic; D004124:p-Dimethylaminoazobenzene / Q000031:analogs & derivatives
D052160:Benzothiazoles; D002273:Carcinogens; D007527:Isoenzymes; D012333:RNA, Messenger; D013844:Thiazoles; C012103:N,N-dimethyl-4-(6-benzothiazolylazo)aniline; D004052:Diethylnitrosamine; D004124:p-Dimethylaminoazobenzene; D005982:Glutathione Transferase