This study characterizes
glutathione (GSH) S-
transferase (GST)
isoenzymes of the liver and forestomach of the female A/J mouse and compares their specificities in catalyzing the conjugation of GSH with 7beta,8alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9, 10-tetrahydrobenzo[a]
pyrene (anti-
BPDE), the ultimate carcinogenic metabolite of
benzo[a]pyrene (BP). The GST activity in female A/J mouse liver was expressed by a minimum of seven
isoenzymes which arose from different homo- or heterodimeric combinations of at least two alpha class (designated as alpha1 and alpha4), four micro class (micro1 to micro4), and one pi class GST subunit. The GST
isoenzyme composition of A/J mouse forestomach appeared to be different from that of the liver. For example, while GST
isoenzymes containing micro3 and micro4 type subunits were selectively expressed in the liver, an alpha class heterodimeric GST
isoenzyme (containing alpha2 and alpha3 subunits) was expressed in the forestomach but could not be detected in the liver. The (+)-anti-
BPDE appeared to be a better substrate than the (-)-enantiomer for all
GSTs, except for
isoenzymes containing the alpha4 type GST subunit. The murine pi class GST
isoenzyme displayed relativey higher specific activity toward (+)-anti-
BPDE compared to other
GSTs. The specific activities of mouse
GSTs toward (+)-anti-
BPDE were in the order of pi > micro > alpha. These results suggest that the pi class GST
isoenzyme may play an important role in providing protection against BP-induced
cancer. Therefore, it seems logical to postulate that the ability of a chemoprotector to increase the expression of GST pi may be an important determinant of its effectiveness against BP-induced
cancer. To test the validity of this contention, we have determined the effects on hepatic and forestomach GST
isoenzyme/subunit expression of three naturally occurring organosulfides (OSCs) from garlic, which significantly differ in their effectiveness against BP-induced forestomach
cancer. Treatment of mice with
diallyl sulfide (
DAS) and
diallyl trisulfide (DATS), which are potent inhibitors of BP-induced fore-
stomach cancer in mice, resulted in a significant increase in hepatic and forestomach GST activity toward anti-
BPDE. On the contrary, this activity was not increased in either organ by
dipropyl sulfide (DPS), which is ineffective against BP-induced forestomach
cancer. The chemopreventive efficacy of these OSCs correlated with their ability to increase the expression of GST pi. For example,
DAS treatment resulted in approximate increases of 1.7- and 2.2-fold in hepatic and forestomach GST pi expression, respectively, over the control. Treatment of mice with DATS, which is a relatively more potent inhibitor of BP-induced forestomach
cancer than
DAS, resulted in about 3.8- and 3.2-fold increases, respectively, in hepatic and forestomach GST pi expression over the control. On the contrary, the expression of hepatic and forestomach GST pi was increased only marginally (10-20%) upon DPS administration. In conclusion, the results of the present study suggest that induction of GST pi can be used as a bioassay for screening potential inhibitors of BP-induced
cancer.