Glutathione S-transferases of female A/J mouse liver and forestomach and their differential induction by anti-carcinogenic organosulfides from garlic.
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.
Hu
X
X
Cancer Research Laboratory, Mercy Hospital, Pittsburgh, Pennsylvania, 15219, USA.
Benson
P J
PJ
Srivastava
S K
SK
Mack
L M
LM
Xia
H
H
Gupta
V
V
Zaren
H A
HA
Singh
S V
SV
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D004790:Enzyme Induction; D005260:Female; D005737:Garlic / Q000737:chemistry; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008969:Molecular Sequence Data; D010946:Plants, Medicinal; D013270:Stomach / Q000187:drug effects / Q000201:enzymology*; D013379:Substrate Specificity; D013440:Sulfides / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D007527:Isoenzymes; D013440:Sulfides; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D005982:Glutathione Transferase; D005978:Glutathione