Abstract
Cisplatin is one of the most widely used chemotherapeutic drugs for the treatment of cancer. Unfortunately, one of its major side effects is permanent hearing loss. Here, we show that glutathione transferase α4 (GSTA4), a member of the Phase II detoxifying enzyme superfamily, mediates reduction of cisplatin ototoxicity by removing 4-hydroxynonenal (4-HNE) in the inner ears of female mice. Under cisplatin treatment, loss of Gsta4 results in more profound hearing loss in female mice compared to male mice. Cisplatin stimulates GSTA4 activity in the inner ear of female wild-type, but not male wild-type mice. In female Gsta4−/− mice, cisplatin treatment results in increased levels of 4-HNE in cochlear neurons compared to male Gsta4−/− mice. In CBA/CaJ mice, ovariectomy decreases mRNA expression of Gsta4, and the levels of GSTA4 protein in the inner ears. Thus, our findings suggest that GSTA4-dependent detoxification may play a role in estrogen-mediated neuroprotection.
Highlights
Cisplatin is one of the most widely used chemotherapeutic drugs for the treatment of cancer
Loss of Gsta[4] results in more profound hearing loss in female mice compared to male mice
Because robust GSTA4 immunostaining was detected in the stria vascularis (SV) (Fig. 1k–m), we investigated whether loss of Gsta[4] leads to reduced SV thickness in the apical, middle, and basal cochlear regions of female or male mice under cisplatin treatment
Summary
Cisplatin is one of the most widely used chemotherapeutic drugs for the treatment of cancer. We show that glutathione transferase α4 (GSTA4), a member of the Phase II detoxifying enzyme superfamily, mediates reduction of cisplatin ototoxicity by removing 4-hydroxynonenal (4-HNE) in the inner ears of female mice. Cells possess a wide range of detoxification enzymes capable of removing thousands of naturally occurring toxins and foreign chemicals[1,2,3] The metabolism of those toxic compounds is generally divided into phase I and phase II reactions. A toxic herbicide known to induce oxidative stress and cell death, Gsta[4] null mice exhibited reduced survival compared to wild-type (WT) mice These reports indicate that GSTA4 plays an important role in aging and cellular survival under oxidative stress conditions
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