Journal Article

GSTA4 mediates reduction of cisplatin ototoxicity in female mice

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

2019

Overview

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. A common complication of cisplatin-based chemotherapy is hearing loss. Here, Park et al. show that glutathione transferase α4 (GSTA4) contributes to reducing cisplatin toxicity in the inner ear of female mice by removing 4-hydroxynonenal (4-HNE).

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 14 / 14/19 / 14/63 / 38 / 38/77 / 4-Hydroxynonenal / 631/378 / 631/378/2619 / 631/378/2619/1387 / 631/67 / 631/67/68 / 64 / 64/60 / 82/51 / 9/30 / Animals / Auditory Threshold - drug effects / Capillaries - pathology / Chemotherapy / Cisplatin / Cisplatin - adverse effects / Cochlea / Cochlea - enzymology / Cochlea - pathology / Cochlea - physiopathology / Crosses, Genetic / Detoxification / DNA Damage - genetics / Ear / Ears & hearing / Estrogens / Evoked Potentials, Auditory, Brain Stem - drug effects / Female / Gene expression / Gene Expression Regulation - drug effects / Glutathione / Glutathione transferase / Glutathione Transferase - deficiency / Glutathione Transferase - metabolism / Hearing loss / Hearing Loss - complications / Hearing Loss - enzymology / Hearing Loss - physiopathology / Humanities and Social Sciences / Inner ear / Male / Menopause / Mice, Inbred CBA / multidisciplinary / Neuroprotection / Ototoxicity / Ototoxicity - complications / Ototoxicity - enzymology / Ototoxicity - pathology / Ototoxicity - physiopathology / Ovariectomy / Oxidative Stress - drug effects / Reduction / RNA, Messenger - genetics / RNA, Messenger - metabolism / Rodents / Science / Science (multidisciplinary) / Side effects / Spiral Ganglion - drug effects / Spiral Ganglion - pathology