Anomalous elevation of glutathione S-transferase P-form (GST-P) in the elementary process of epigenetic initiation of chemical hepatocarcinogenesis in rats.
The molecular mechanism of the specific expression of glutathione S-transferase P-form (GST-P) in the rat hepatic preneoplastic foci and "GST-P-positive" single cells requires elucidation. Immunochemical and stereological analyses revealed that the enzyme level in preneoplastic foci was 150-250-fold (6.7 +/- 2.4 mg/g liver and 0.29 +/- 0.1 mM subunits) higher than in normal cells. GST-P content in the single cells was higher than in preneoplastic foci, as determined by densitometry. In addition, the single cells were larger in cell diameter and area, corresponding to 2-3-fold increase in cell volume, relative to normal cells, but showed a significant shrinkage of their nuclei. Prior to the induction of single cells in the liver by diethylnitrosamine (DEN), microsomes were severely damaged as reflected by the low yield (approximately 60% that of untreated controls) after 2 h of DEN injection. Considering that GST-P is mainly a binding protein for GSH conjugates of endogenous carcinogens, together with our findings of morphological expansion, low viability of single cells and microsomal damage, our results suggest anomalous elevation of the ligand counterparts to lethal levels in preneoplastic cells, especially in single cells. We propose that the epigenetic mechanism rather than the genetic mechanism could account for GST-P induction in hepatocytes.
Satoh
Kimihiko
K
Department of Organic Function, Hirosaki University, School of Health Science, Hon-Cho 66-1, Hirosaki 036-8564, Japan. kisatoh@cc.hirosaki-u.ac.jp
Hatayama
Ichiro
I
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D002467:Cell Nucleus / Q000473:pathology; D048429:Cell Size / Q000502:physiology; D002478:Cells, Cultured; D004052:Diethylnitrosamine / Q000633:toxicity; D004573:Electrolytes; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D011230:Precancerous Conditions / Q000201:enzymology* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D000477:Alkylating Agents; D004573:Electrolytes; C034130:ORALIT; D004052:Diethylnitrosamine; D005982:Glutathione Transferase; D005952:Glucose-6-Phosphatase