Mj. Stalker et al., REDUCED EXPRESSION OF GLUTATHIONE-S-TRANSFERASE YB2 DURING PROGRESSION OF CHEMICALLY-INDUCED HEPATOCELLULAR CARCINOMAS IN FISCHER-344 RATS, Hepatology, 20(1), 1994, pp. 149-158
We followed the expression of several glutathione S-transferase subuni
ts in altered foci, liver neoplasms and metastases produced in male Fi
scher 344 rats by a modified Solt-Farber protocol, to determine whethe
r components of the resistant phenotype are lost during neoplastic pro
gression. At 6 mo after initiation, altered foci and persistent nodule
s 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, alth
ough most altered foci exhibited little change in glutathione S-transf
erase Yb2 (mu-class) subunit expression, 5% of Yf-positive foci and no
dules 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 e
xpression. These differences in glutathione S-transferase subunit expr
ession were confirmed by quantitative analysis by reverse-phase HPLC o
f S-hexylglutathione affinity-purified glutathione S-transferases from
advanced tumors. Cytosolic glutathione 8-transferase activity for tra
ns-4-phenyl-3-buten-2-one in advanced tumors ranged from 42% to 66% of
the activity in matched surrounding liver, whereas glutathione 8-tran
sferase activities for 1-chloro-2,4-dinitrobenzene were increased by 1
40% to 161%. These studies demonstrate that progression of hepatocellu
lar carcinomas in the resistant hepatocyte model of carcinogenesis in
which several glutathione S-transferase subunits are induced is associ
ated with the loss of a major constitutive mu-class hepatic glutathion
e S-transferase. Although the mechanism and role of the reduction or l
oss of glutathione 8-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 furthe
r DNA damage by presently unknown environmental or endogenous compound
s that are normally detoxified preferentially by glutathione 8-transfe
rase isoenzymes containing this subunit.