Living organisms are continuously exposed to and must defend against naturally occurring toxins and non- nutrient foreign chemicals (1-3). Cells possess a wide range of detoxification enzymes capable of removing thousands of toxic and foreign compounds. The glutathione transferase (GST) detoxification system converts a non-polar toxic compound into a more water-soluble and less toxic form by conjugating the toxic compound to reduced glutathione by a variety of GST enzymes. GSTs are a superfamily of enzymes that are divided into several classes on the basis of their primary structure (1-3). Because of their cytoprotective role and involvement in the development of resistance to anti-cancer agents, GSTs have become attractive drug targets. Epidemiological studies found a significant association between age-related hearing loss and GSTT1 and GSTM1 null polymorphisms was found in a Finnish population (5) and a Hispanic population (6). McElwee et al (7) conducted a cross-species comparative analysis to compare gene expression changes in long-lived worms, flies, and mice, and found that GST and other cellular detoxification gene categories were significantly up- regulated in long-lived members of the three species, suggesting the GST detoxification system plays a major role in longevity or protection against aging in multiple species. Consistent with these reports, our preliminary studies found that long-living calorie-restricted C57BL/6 mice display increased expression of Gsta4, Gstm1, Gstm5, and Gstt1 genes in the cochlea. Collectively, these results suggest that GST detoxification enzymes may play an important role in ototoxicity. Cisplatin, a platinum-containing compound, is one of the most widely used chemotherapeutic agents (8-10). Evidence indicates that one-third of all cisplatin-treated patients develop hearing loss. Such hearing impairment is dose-dependent, irreversible, and associated with loss of hair cells. Wheeler et al (11) performed meta-analyses of over 3 million single-nucleotide polymorphisms (SNPs) for cisplatin-induced cytotoxicity in 608 lymphoblastoid cell lines from seven HapMap panels. The study found that increased GSTM1 and GSTT1 expression was associated with increased cisplatin resistance. Our preliminary study also found that cisplatin treatment up-regulates GSTA and GSTM genes in mouse cochlear organotypic cultures. Yet, how the cochlear detoxification system fights such ototoxic drugs at the molecular level remain poorly understood. The overall goal of our research proposal is to provide new basic knowledge of the molecular basis for the cochlear detoxification system and its role in the elimination of foreign chemicals throughout the lifespan.
Living organisms are continuously exposed to and must defend against naturally occurring toxins and non- nutrient foreign chemicals (1-3). The glutathione transferase (GST) detoxification system converts a non-polar toxic compound into a more water-soluble and less toxic form by conjugating the toxic compound to reduced glutathione by a variety of GST enzymes. The overall goal of our research proposal is to provide new basic knowledge of the molecular basis for the cochlear detoxification system and its role in the elimination of non-nutrient foreign chemicals and naturally occurring toxins throughout the lifespan. Understanding the mechanism of action of cochlear detoxification may define novel therapeutic approaches for human hearing loss induced by drugs, chemicals, or naturally occurring toxins.
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