Structure and Gene Regulation of Human Glutathione Transferase GSTT1-1 [ 2003 - 2005 ]

Research Grant

Researchers: Dr Ricarda Thier (Principal investigator)

Brief description Glutathione transferases (GSTs) play a critical role cellular detoxification system. They belong to the phase II enzymes of the xenobiotic metabolism and conjugate a wide range of drugs and chemicals with glutathione to increase water solubility and thereby enhancing their elimination. The conjugation with glutathione is considered an important detoxification route for most chemicals. However, it has been shown that in many cases this pathway leads to metabolites that are more toxic than the initial chemical or drug. The gene deletion of the particular human GSTT1 gene results in total loss of this particular enzyme activity in all tissues of homozygous null genotype individuals. This phenotype is called non-conjugator . Non-conjugators seem to have a higher risk to develop certain cancer types, e.g. urinary bladder cancer or brain tumours, while they seem to be less susceptible for others, e.g. liver. Occupational exposure to chemicals is of relevance in such relationships because the GSTT1 enzyme metabolises a wide range of industrial chemicals including solvents but also monomers used in the production of rubbers and other polymers. In addition, GSTT1 seems to influence the efficay of cancer chemotherapy by inactivating certain anti-cancer drugs, eg. BCNU, that is predominantly use in treatment of brain tumours. The aims of this study include the characterisation of the tissue-specific activity and the influence of xenobiotics on the protein levels of this enzyme. The study leads to a better understanding of the etiology of exposure related cancers and of the mechanisms of resistance to cancer chemotherapy. Such knowledge allows the development of concepts for the optimisation of efficacy and minimisation of side effects in chemotherapy.

Funding Amount $AUD 250,500.00

Funding Scheme NHMRC Project Grants

Notes New Investigator Grant