GSTA4 mediates reduction of cisplatin ototoxicity in female mice

Abstract

AbstractCisplatin 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 ofGsta4results 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 femaleGsta4−/−mice, cisplatin treatment results in increased levels of 4-HNE in cochlear neurons compared to maleGsta4−/−mice. In CBA/CaJ mice, ovariectomy decreases mRNA expression ofGsta4, 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.