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 and Shinichi Someya ()
Additional contact information
Hyo-Jin Park: University of Florida
Mi-Jung Kim: University of Florida
Christina Rothenberger: University of Florida
Ashok Kumar: University of Florida
Edith M. Sampson: University of Florida
Dalian Ding: State University of New York at Buffalo
Chul Han: University of Florida
Karessa White: University of Florida
Kevin Boyd: University of Florida
Senthilvelan Manohar: State University of New York at Buffalo
Yong-Hwan Kim: Barrow Neurological Institute
Maria S. Ticsa: University of Florida
Aaron S. Gomez: University of Florida
Isabela Caicedo: University of Florida
Upal Bose: University of Florida
Paul J. Linser: University of Florida
Takuya Miyakawa: University of Tokyo
Masaru Tanokura: University of Tokyo
Thomas C. Foster: University of Florida
Richard Salvi: State University of New York at Buffalo
Shinichi Someya: University of Florida

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12073-0

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