Toxicogenomics of Glutathione S-transferase (GST) Gene Family Members: Chemical-gene Interactions and Potential Implications of Gene Deletions

A toxicogenomic analysis of GSTT1 and GSTM1 genes was performed in this study. Diseases, gene-chemical interactions, expression profiles, and biological processes associated with both genes were analyzed using data and tools from STRING and The Comparative Toxicogenomics Database. Protein interaction networks detailed the participation of Gstt1 (Mus musculus) and GSTM1 (Homo sapiens) in the detoxification of xenobiotics. Metabolism of long-chain fatty acids, glutathione and multiple xenobiotics were observed among the top-10 biological processes in GST protein networks. Different types of cancer, chromosomal aberrations, and liver damage were among the top-10 diseases/conditions associated with the genes. A diversity of environmental pollutants was listed among the top-10 chemicals acting on GSTT1 or GSTM1. In total, 167 chemicals interact with both genes. However, out of the 270 chemical agents acting on GSTT1, 103 (38.15 %) interact exclusively with this gene. Out of the 472 chemicals acting on GSTM1, 305 (64.62 %) interact exclusively with this gene. These results indicate that the GST enzyme system is not completely redundant, helping to explain why GSTT1 and GSTM1 deletions are phenotypically relevant. Most chemicals affect the expression of GSTT1 and GSTM1 in a complex manner, especially in the GSTT1 case (p = 0.013). A significantly higher percentage of chemicals increased GSTM1 expression (29.81 %) compared to GSTT1 (20.96 %, p < 0.001). In brief, GSTT1 and/or GSTM1 deletions can affect the metabolism of hundreds of xenobiotics, helping to explain why these genes influence the risk of a wide diversity of cell phenotypes and pathological conditions.