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Gene Review

Gstp1  -  glutathione S-transferase pi 1

Rattus norvegicus

Synonyms: Chain 7, GST 7-7, GST class-pi, GST-P, Glutathione S-transferase P, ...
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Disease relevance of Gstp1

  • We have isolated the rat placental-type glutathione S-transferase (GST-P) gene from a lambda phage library using GST-P cDNA clone, pGP5 (Sugioka, Y., Kano, T., Okuda, A., Sakai, M., Kitagawa, T., and Muramatsu, M. (1985) Nucleic Acids Res. 13, 6049-6057), as a probe [1].
  • A cDNA library prepared from poly(A)+ RNA of 2-acetylaminofluorene (AAF) induced rat hepatocellular carcinoma was screened by synthetic DNA probes deduced from a partial amino acid sequence of glutathione S-transferase P subunit that had been isolated from the tumor by two-dimensional gel electrophoresis [2].
  • Compared to their respective controls, significant increases in GSTP-positive hepatocytes were observed in male rats administered FB1 i.p. at 10 mg/kg body weight/day for 4 days, as well as in male and female rats treated with 35 and 75 mg/kg body weight/day FB1 p.o. for 11 days [3].
  • Therefore, our data suggest that in a manner similar to known genotoxic carcinogens, FB1 has the capacity to initiate GSTP-positive hepatocytes with their subsequent development into GSTP mini-foci at exposure levels that induce enhanced hepatocyte proliferation in response to liver toxicity [3].
  • A strong positive correlation was also observed between the extent of fibrosis in the livers of these animals and the hepatic burden of GST-P-positive foci, implying that cytotoxicity is associated with the tumorigenic process [4].

High impact information on Gstp1

  • Glutathione transferase P (GST-P; glutathione transferase, EC is known to be specifically expressed at high levels in precancerous lesions and in hepatocellular carcinomas from a very early phase of chemically induced hepatocarcinogenesis in the rat [5].
  • The almost invariable occurrence of this phenotype in these lesions strongly suggests a mechanism by which GST-P gene is activated together with a crucial transforming gene of liver cells [5].
  • In each of three independent lines tested, liver foci and nodules produced by chemical carcinogens (Solt-Farber procedure) were found to express high levels of chloramphenicol acetyltransferase activity, indicating clearly that the GST-P gene is activated by a trans mechanism during hepatocarcinogenesis [5].
  • We have analyzed the cis-acting regulatory DNA elements of the placental rat glutathione S-alkyltransferase (GST-P) gene [6].
  • Two enhancing elements were located 2.5 and 2.2 kilobases upstream from the transcription start site and designated GST-P enhancers I and II (GPEI and GPEII, respectively) [6].

Chemical compound and disease context of Gstp1


Biological context of Gstp1


Anatomical context of Gstp1

  • In experiment 1, 2% KA feeding induced significant increases in numbers (22.3 +/- 13.0 vs 8.5 +/- 3.4 in the 0%) and areas (0.37 +/- 0.29 vs 0.05 +/- 0.03 in the 0%) of glutathione-S-transferase P form (GST-P)-positive foci and toxic changes such as vacuolation of hepatocytes and microgranulomas [13].
  • In accordance with the above observation, endogenous GST-P gene was found to be stimulated when the rat fibroblast line 3Y1 was treated with phorbol 12-O-tetradecanoate 13-acetate [6].
  • Phorbol 12-O-tetradecanoate 13-acetate enhanced the expression of the transfected GST-P gene to a much higher degree in HeLa cells than in the hepatoma cells, which constitutively expressed the endogenous GST-P [6].
  • GST-P expression in preneoplastic lesions is suppressed by peroxisome proliferators [14].
  • Bile duct cells were positive for GST-P and negative for transforming growth factor beta 1, whereas cells in the periductal space were positive for both of these transcripts [15].

Associations of Gstp1 with chemical compounds

  • In particular, the Ya subunit of glutathione S-transferase B, the Yb subunit of glutathione S-transferase A, as well as the three isoelectric point variants of the Yp subunit of glutathione S-transferase P were increased 2-, 4-, and 7-fold, respectively, in preneoplastic and neoplastic nodules [16].
  • In contrast, the Yp subunits were not detected in any of the CP nodules either on the two-dimensional polyacrylamide gel electrophoresis gels themselves or following Western transfer and immunoblot analysis with antibody against GST-P [17].
  • PCNA labeling in GSTP-positive foci was not affected by BHT [18].
  • The GST-P protein has been previously shown to facilitate the excretion of sodium arsenite [As(III)] from SA7 cells [19].
  • Hepatocarcinogenesis initiated with N-nitrosodiethylamine (DEN) and that initiated by feeding of a choline-deficient, L-amino acid-defined (CDAA) diet were compared in transgenic male Wistar rats harboring a rat glutathione S-transferase placental form (GST-P) gene (GST-P-Tg rats) and non-transgenic (N-Tg) rats [20].

Regulatory relationships of Gstp1


Other interactions of Gstp1

  • In experiment 2, numbers (0.65 +/- 0.57 vs 0.17 +/- 0.28 in the 0%) and areas (0.005 +/- 0.005 vs 0.0007 +/- 0.0012 in the 0%) of GST-P-positive foci and hepatocellular proliferating cell nuclear antigen (PCNA) expression (3.8 +/- 2.3 vs 2.6 +/- 0.7 in the 0%) were significantly increased by the 2% treatment [13].
  • Expression of TGF-alpha during promotion of neoplastic development from GST-P-positive foci in rat chemical hepatocarcinogenesis was investigated [21].
  • These results suggest that expression of cytokeratin 18, a later phenotypic change in foci than induction of GST-P and GGT, correlates more closely with tumour outcome in this model [22].
  • Five weeks after the DEN treatment, numbers and sizes of gamma-glutamyltransferase (GGT)- or GST-P-positive lesions and 8-hydroxyguanine (8-OHG) levels in the livers were significantly less in GST-P-Tg rats than in N-Tg rats [20].
  • The numbers of cx 32-positive spots per hepatocyte in GST-P-negative foci were clearly decreased, reaching 65.4% at week 20 and 51.8% at week 30 of values for surrounding normal hepatocytes [23].

Analytical, diagnostic and therapeutic context of Gstp1


  1. The structure of the rat glutathione S-transferase P gene and related pseudogenes. Okuda, A., Sakai, M., Muramatsu, M. J. Biol. Chem. (1987) [Pubmed]
  2. Cloning and the nucleotide sequence of rat glutathione S-transferase P cDNA. Suguoka, Y., Kano, T., Okuda, A., Sakai, M., Kitagawa, T., Muramatsu, M. Nucleic Acids Res. (1985) [Pubmed]
  3. Glutathione S-transferase-placental form expression and proliferation of hepatocytes in fumonisin B1-treated male and female Sprague-Dawley rats. Mehta, R., Lok, E., Rowsell, P.R., Miller, J.D., Suzuki, C.A., Bondy, G.S. Cancer Lett. (1998) [Pubmed]
  4. Transient intervention with oltipraz protects against aflatoxin-induced hepatic tumorigenesis. Bolton, M.G., Muñoz, A., Jacobson, L.P., Groopman, J.D., Maxuitenko, Y.Y., Roebuck, B.D., Kensler, T.W. Cancer Res. (1993) [Pubmed]
  5. Trans-activation of glutathione transferase P gene during chemical hepatocarcinogenesis of the rat. Morimura, S., Suzuki, T., Hochi, S., Yuki, A., Nomura, K., Kitagawa, T., Nagatsu, I., Imagawa, M., Muramatsu, M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  6. Multiple regulatory elements and phorbol 12-O-tetradecanoate 13-acetate responsiveness of the rat placental glutathione transferase gene. Sakai, M., Okuda, A., Muramatsu, M. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  7. Lack of expression of glutathione-S-transferase P, gamma-glutamyl transpeptidase, and alpha-fetoprotein messenger RNAs in liver tumors induced by peroxisome proliferators. Rao, M.S., Nemali, M.R., Usuda, N., Scarpelli, D.G., Makino, T., Pitot, H.C., Reddy, J.K. Cancer Res. (1988) [Pubmed]
  8. Fibrosis accelerates the development of enzyme-altered lesions in the rat liver. Sakaida, I., Hironaka, K., Uchida, K., Suzuki, C., Kayano, K., Okita, K. Hepatology (1998) [Pubmed]
  9. Cell proliferation induced by triiodothyronine in rat liver is associated with nodule regression and reduction of hepatocellular carcinomas. Ledda-Columbano, G.M., Perra, A., Loi, R., Shinozuka, H., Columbano, A. Cancer Res. (2000) [Pubmed]
  10. Lack of hepatocarcinogenic potential of acetaminophen in rats with liver damage associated with a choline-devoid diet. Maruyama, H., Takashima, Y., Murata, Y., Nakae, D., Eimoto, H., Tsutsumi, M., Denda, A., Konishi, Y. Carcinogenesis (1990) [Pubmed]
  11. Isolation of glutathione S-transferase P-positive hepatocytes from carcinogen treated rats by use of ethacrynic acid as selecting agent. Stenius, U., Warholm, M., Martens, U., Högberg, J. Carcinogenesis (1994) [Pubmed]
  12. Induction of 8-hydroxydeoxyguanosine but not initiation of carcinogenesis by redox enzyme modulations with or without menadione in rat liver. Denda, A., Sai, K.M., Tang, Q., Tsujiuchi, T., Tsutsumi, M., Amanuma, T., Murata, Y., Nakae, D., Maruyama, H., Kurokawa, Y. Carcinogenesis (1991) [Pubmed]
  13. Enhancement of hepatocarcinogenesis by kojic acid in rat two-stage models after initiation with N-bis(2-hydroxypropyl)nitrosamine or N-diethylnitrosamine. Takizawa, T., Imai, T., Onose, J., Ueda, M., Tamura, T., Mitsumori, K., Izumi, K., Hirose, M. Toxicol. Sci. (2004) [Pubmed]
  14. Suppression of rat glutathione transferase P expression by peroxisome proliferators: interaction between Jun and peroxisome proliferator-activated receptor alpha. Sakai, M., Matsushima-Hibiya, Y., Nishizawa, M., Nishi, S. Cancer Res. (1995) [Pubmed]
  15. Cellular and molecular changes in the early stages of chemical hepatocarcinogenesis in the rat. Evarts, R.P., Nakatsukasa, H., Marsden, E.R., Hsia, C.C., Dunsford, H.A., Thorgeirsson, S.S. Cancer Res. (1990) [Pubmed]
  16. Sequential analysis of chemically induced hepatoma development in rats by two dimensional electrophoresis. Wirth, P.J., Benjamin, T., Schwartz, D.M., Thorgeirsson, S.S. Cancer Res. (1986) [Pubmed]
  17. Coordinate polypeptide expression during hepatocarcinogenesis in male F-344 rats: comparison of the Solt-Farber and Reddy models. Wirth, P.J., Rao, M.S., Evarts, R.P. Cancer Res. (1987) [Pubmed]
  18. The effect of butylated hydroxytoluene on the growth of enzyme-altered foci in male Fischer 344 rat liver tissue. Lok, E., Mehta, R., Jee, P., Laver, G., Nera, E.A., McMullen, E., Clayson, D.B. Carcinogenesis (1995) [Pubmed]
  19. Identification of galectin I and thioredoxin peroxidase II as two arsenic-binding proteins in Chinese hamster ovary cells. Chang, K.N., Lee, T.C., Tam, M.F., Chen, Y.C., Lee, L.W., Lee, S.Y., Lin, P.J., Huang, R.N. Biochem. J. (2003) [Pubmed]
  20. Inhibition of early-phase exogenous and endogenous liver carcinogenesis in transgenic rats harboring a rat glutathione S-transferase placental form gene. Nakae, D., Denda, A., Kobayashi, Y., Akai, H., Kishida, H., Tsujiuchi, T., Konishi, Y., Suzuki, T., Muramatsu, M. Jpn. J. Cancer Res. (1998) [Pubmed]
  21. Possible tumor development from double positive foci for TGF-alpha and GST-P observed in early stages on rat hepatocarcinogenesis. Kitano, M., Wada, J., Ariki, Y., Kato, M., Wanibuchi, H., Morimura, K., Hidaka, T., Hosoe, K., Fukushima, S. Cancer Sci. (2006) [Pubmed]
  22. Chemoprevention of aflatoxin B1-induced carcinogenesis by indole-3-carbinol in rat liver--predicting the outcome using early biomarkers. Manson, M.M., Hudson, E.A., Ball, H.W., Barrett, M.C., Clark, H.L., Judah, D.J., Verschoyle, R.D., Neal, G.E. Carcinogenesis (1998) [Pubmed]
  23. Immunohistochemical demonstration of the gap junctional protein connexin 32 and proliferating cell nuclear antigen in glutathione S-transferase placental form-negative lesions of rat liver induced by diethylnitrosamine and clofibrate. Ito, S., Tateno, C., Tuda, M., Yoshitake, A. Toxicologic pathology. (1996) [Pubmed]
  24. DNA damage triggers imbalance of proliferation and apoptosis during development of preneoplastic foci in the liver of Long-Evans Cinnamon rats. Jia, G., Tohyama, C., Sone, H. Int. J. Oncol. (2002) [Pubmed]
  25. alpha(2)-Macroglobulin: a novel cytochemical marker characterizing preneoplastic and neoplastic rat liver lesions negative for hitherto established cytochemical markers. Sukata, T., Uwagawa, S., Ozaki, K., Sumida, K., Kikuchi, K., Kushida, M., Saito, K., Morimura, K., Oeda, K., Okuno, Y., Mikami, N., Fukushima, S. Am. J. Pathol. (2004) [Pubmed]
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