Reduced expression of glutathione S-transferase Yb2 during progression of chemically induced hepatocellular carcinomas in Fischer 344 rats.
We followed the expression of several glutathione S-transferase subunits in altered foci, liver neoplasms and metastases produced in male Fischer 344 rats by a modified Solt-Farber protocol, to determine whether components of the resistant phenotype are lost during neoplastic progression. At 6 mo after initiation, altered foci and persistent nodules displayed increased immunohistochemical expression of glutathione S-transferase subunits Yf (pi-class), Ya (alpha-class) and Yb1 (mu-class) in comparison with normal or surrounding liver tissue. However, although most altered foci exhibited little change in glutathione S-transferase Yb2 (mu-class) subunit expression, 5% of Yf-positive foci and nodules were partially or completely deficient in Yb2 expression. At 12 and 18 mo after initiation, most grossly visible hepatocellular tumors retained induced expression of glutathione S-transferase subunits Yf, Ya and Yb1, but 63% of the carcinomas, 88% of the primary metastatic carcinomas and 94% of the pulmonary metastases were deficient in Yb2 expression. These differences in glutathione S-transferase subunit expression were confirmed by quantitative analysis by reverse-phase HPLC of S-hexylglutathione affinity-purified glutathione S-transferases from advanced tumors. Cytosolic glutathione S-transferase activity for trans-4-phenyl-3-buten-2-one in advanced tumors ranged from 42% to 66% of the activity in matched surrounding liver, whereas glutathione S-transferase activities for 1-chloro-2,4-dinitrobenzene were increased by 140% to 161%. These studies demonstrate that progression of hepatocellular carcinomas in the resistant hepatocyte model of carcinogenesis in which several glutathione S-transferase subunits are induced is associated with the loss of a major constitutive mu-class hepatic glutathione S-transferase. Although the mechanism and role of the reduction or loss of glutathione S-transferase Yb2 during malignant progression are unknown, we propose that loss of glutathione S-transferase Yb2 in some preneoplastic populations of hepatocytes might be conducive to further DNA damage by presently unknown environmental or endogenous compounds that are normally detoxified preferentially by glutathione S-transferase isoenzymes containing this subunit.
Department of Pathology, University of Guelph, Ontario, Canada.
M J
MJ
Stalker
T E
TE
Kocal
B A
BA
Quinn
S G
SG
Gordon
M A
MA
Hayes
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000201:enzymology; D005982:Glutathione Transferase / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology / Q000556:secondary; D008297:Male; D010641:Phenotype; D051381:Rats; D011916:Rats, Inbred F344
D007527:Isoenzymes; D005982:Glutathione Transferase