GLUTATHIONE S-TRANSFERASES OF FEMALE A J MOUSE-LIVER AND FORESTOMACH AND THEIR DIFFERENTIAL INDUCTION BY ANTICARCINOGENIC ORGANOSULFIDES FROM GARLIC/

This study characterizes glutathione (GSH) S-transferase (GST) isoenzy mes of the liver and forestomach of the female A/J mouse and compares their specificities in catalyzing the conjugation of GSH with 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyren e (anti-BPDE), the ultimate carcinogenic metabolite of benzo[a]pyrene (BP). The GST activity in female A/J mouse liver was expressed by a mi nimum of seven isoenzymes which arose from different homoor heterodime ric combinations of at least two alpha class (designated as alpha 1 an d alpha 4), four mu class (mu 1 to mu 4), and one pi class GST subunit . The GST isoenzyme composition of A/J mouse forestomach appeared to b e different from that of the liver. For example, while GST isoenzymes containing mu 3 and mu 4 type subunits were selectively expressed in t he liver, an alpha class heterodimeric GST isoenzyme (containing alpha 2 and alpha 3 subunits) was expressed in the forestomach but could no t 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 alpha 4 type GST subunit. The murine a class GST isoenz yme 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 > mu > alpha. These results sugge st that the a class GST isoenzyme may play an important role in provid ing protection against BP-induced cancer. Therefore, it seems logical to postulate that the ability of a chemoprotector to increase the expr ession 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 B P-induced forestomach cancer in mice, resulted in a significant increa se in hepatic and forestomach GST activity toward anti-BPDE. On the co ntrary, this activity was not increased in either organ by dipropyl su lfide (DPS), which is ineffective against BP-induced forestomach cance r. The chemopreventive efficacy of these OSCs correlated with their ab ility 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. Treatm ent 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 expre ssion over the control. On the contrary, the expression of hepatic and forestomach GST pi was increased only marginally (10-20%) upon DPS ad ministration. In conclusion, the results of the present study suggest that induction of GST pi can be used as a bioassay for screening poten tial inhibitors of BP-induced cancer. (C) 1996 Academic Press, Inc.