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Glutathione transferases (GSTs) are abundant proteins with multiple functions in human tissues. The research proposal is focused on enzymatic activities that play prominent roles in various aspects of cancer, from prevention to clinical treatment of patients. Fruits and vegetables contain compounds inducing cellular synthesis of detoxication enzymes, including GSTs. Animal models have shown that some of them have potent anticarcinogenic activities. These findings are in accordance with epidemiological findings of a correlation between consumption of vegetables and lower incidence of cancer. Many of the cancerpreventive compounds are substrates of GSTs, but the differential roles of the multiple forms of GSTs and their possible contributions to promote transcription of genes encoding protective enzymes is unknown. In tumor cells, GSTs contribute to drug resistance by inactivating alkylating cytostatic drugs. There is growing evidence for alternative splicing of GST genes, and we are analyzing tumor cells for the presence of alternative forms of GSTs displaying enhanced activity with anticancer drugs. We have strong indications for a role of GST A3-3 in the biosynthesis of steroid hormones, and we are exploring this putative therapeutic target for hormone-dependent prostate and breast cancer. In addition, prodrugs selectively activated by GSTs in tumors have therapeutic applications in tumors. Finally, recombinant GSTs with enhanced activities against alkylating cytostatic drugs could provide protection to the bone marrow and other sensitive tissues subject to adverse side effects of chemotherapy. In vitro studies show that GSTs with 100-fold enhanced alkyltransferase activity can be generated by directed evolution.

 

References:

Diana S. Hamilton, Xiyun Zhang, Zhebo Ding, Ina Hubatsch, Bengt Mannervik, K.N. Houk, Bruce Ganem and Donald J. Creighton (2003) Mechanism of the glutathione transferase-catalyzed conversion of antitumor 2-crotonyloxymethyl-2-cycloalkenes to GSH adducts, J. Am. Chem. Soc. 125 , 15049-15058.

 

Kristian Dreij, Kathrin Sundberg, Ann-Sofie Johansson, Erik Nordling, Albrecht Seidel, Bengt Persson, Bengt Mannervik and Bengt Jernström (2002) Catalytic activities of human alpha class glutathione transferases toward carcinogenic dibenzo[ a,l ]pyrene diol epoxides, Chem. Res. Toxicol. 15 , 825-831.

 

Ann-Sofie Johansson and Bengt Mannervik (2002) Active-site residues governing high steroid isomerase activity in human glutathione transferase A3-3, J. Biol. Chem. 277 , 16648-16654.

 

Samantha Lien, Anna-Karin Larsson and Bengt Mannervik (2002) The polymorphic human glutathione transferase T1-1, the most efficient glutathione transferase in the denitrosation and inactivation of the anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea, Biochem. Pharmacol. 63 , 191-197.

 

Ann-Sofie Johansson and Bengt Mannervik (2001) Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones, J. Biol. Chem. 276 , 33061-33065.