GSTA4 mediates reduction of cisplatin ototoxicity in female mice

Hyo-Jin Park, Mi-Jung Kim, Christina Rothenberger, Ashok Kumar, Edith M. Sampson, Dalian Ding, Chul Han, Karessa White, Kevin Boyd, Senthilvelan Manohar, Yong-Hwan Kim, Maria S. Ticsa, Aaron S. Gomez, Isabela Caicedo, Upal Bose, Paul J. Linser, Takuya Miyakawa, Masaru Tanokura, Thomas C. Foster, Richard Salvi, Shinichi Someya

doi:10.1038/s41467-019-12073-0

<jats:title>Abstract</jats:title><jats:p>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<jats:italic>Gsta4</jats:italic>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<jats:italic>Gsta4</jats:italic><jats:sup>−/−</jats:sup>mice, cisplatin treatment results in increased levels of 4-HNE in cochlear neurons compared to male<jats:italic>Gsta4</jats:italic><jats:sup>−/−</jats:sup>mice. In CBA/CaJ mice, ovariectomy decreases mRNA expression of<jats:italic>Gsta4</jats:italic>, 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.</jats:p>

GSTA4 mediates reduction of cisplatin ototoxicity in female mice

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