Induction of glutathione S-transferase pi as a bioassay for the evaluation of potency of inhibitors of benzo(a)pyrene-induced cancer in a murine model.
There is a growing need for short-term and cost-effective bioassay to assess the efficacy of potential chemo-preventive agents. We report that the induction of glutathione (GSH) S-transferase pi (mGSTP1-1) by a chemo-preventive agent can be used as a reliable marker to assess its efficacy in retarding chemical carcinogenesis induced by benzo(a)pyrene (BP), which is a widespread environmental pollutant and believed to be a risk factor in human chemical carcinogenesis. This conclusion is based on 1) the relative contribution of mGSTP1-1 of the liver and forestomach of female A/J mice in the detoxification of the ultimate carcinogenic metabolite of BP, (+)-anti-7,8-dihydroxy-9, 10-oxy-7,8,9, 10-tetrahydrobenzo(a)pyrene [(+)-anti-BPDE]; and 2) a positive correlation between the induction of hepatic and forestomach mGSTP1-1 by 5 naturally occurring organosulfides (OSCs) from garlic (diallyl sulfide, diallyl disulfide, diallyl trisulfide, dipropyl sulfide and dipropyl disulfide) and their effectiveness in preventing BP-induced forestomach neoplasia in mice. In the liver, the combined contribution of other GSTs in the detoxification of (+)-anti-BPDE was far less than the contribution of mGSTP1-1 alone. Likewise, in the forestomach, the contribution of mGSTP1-1 far exceeded the combined contribution of other GSTs. Studies on the effects of OSCs against BP-induced forestomach neoplasia revealed a good correlation between their chemo-preventive efficacy and their ability to induce mGSTP1-1 expression in the liver (r = -0.89; p < 0.05) as well as in the forestomach (r = -0.97; p < 0.05). Our results suggest that the induction of mGSTP1-1 may be a reliable marker for evaluating the efficacy of potential inhibitors of BP-induced cancer in a murine model.
Hu
X
X
Cancer Research Laboratory, Mercy Cancer Institute, Mercy Hospital of Pittsburgh, PA 15219, USA.
Benson
P J
PJ
Srivastava
S K
SK
Xia
H
H
Bleicher
R J
RJ
Zaren
H A
HA
Awasthi
S
S
Awasthi
Y C
YC
Singh
S V
SV
D000498:Allyl Compounds / Q000302:isolation & purification / Q000627:therapeutic use; D000818:Animals; D016588:Anticarcinogenic Agents / Q000302:isolation & purification / Q000627:therapeutic use*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001681:Biological Assay / Q000191:economics / Q000379:methods; D002851:Chromatography, High Pressure Liquid; D004220:Disulfides / Q000302:isolation & purification / Q000627:therapeutic use; D004790:Enzyme Induction; D005260:Female; D005737:Garlic / Q000737:chemistry; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis* / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D051379:Mice; D008805:Mice, Inbred A; D010946:Plants, Medicinal; D011407:Propane / Q000031:analogs & derivatives / Q000302:isolation & purification / Q000627:therapeutic use; D012044:Regression Analysis; D013270:Stomach / Q000201:enzymology; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D013440:Sulfides / Q000302:isolation & purification / Q000627:therapeutic use*; D016896:Treatment Outcome
D000498:Allyl Compounds; D016588:Anticarcinogenic Agents; D004220:Disulfides; D007527:Isoenzymes; D013440:Sulfides; C042577:diallyl trisulfide; D001564:Benzo(a)pyrene; C028009:diallyl disulfide; C038491:allyl sulfide; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496557:Gstp1 protein, mouse; C041288:n-propyl disulfide; C087894:dipropyl sulfide; D011407:Propane