单羧酸转运蛋白6通过代谢物摄取介导性别依赖性的顺铂耳毒性
Monocarboxylate transporter 6 mediates sex-dependent cisplatin ototoxicity via metabolite uptake.
文献信息
| PMID | 42933113 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Arthur Germakovski |
| 作者单位 | Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Division of Molecular Biosciences, University at Buffalo State University of New York, Buffalo, New York. |
| 期刊 | Drug metabolism and disposition: the biological fate of chemicals |
| SCI 分区 | Q2 |
| IF | 4.1 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 耳科 |
中文摘要
背景： 顺铂是一种广泛使用的抗癌药物，但高达75%的患者会出现耳毒性，目前尚无完全有效的预防或治疗手段。尽管单羧酸转运蛋白6（MCT6；SLC16A5）的遗传变异已被认为与顺铂诱导的听力损失减轻相关，但这些发现尚未被一致重复，其潜在机制仍不清楚。我们假设MCT6介导一种细胞毒性顺铂代谢物的摄取，且MCT6缺失可提供对顺铂诱导耳毒性的保护。方法：在此我们显示，MCT6选择性介导顺铂代谢物N-乙酰-L-半胱氨酸-顺铂的摄取，并在体内驱动性别依赖性耳毒性。结果：利用遗传学、药代动力学和功能性听觉方法，我们证明Mct6缺陷不改变全身铂暴露，但在雌性而非雄性小鼠中提供对顺铂诱导听力损失的强有力保护。与这一表型一致，Mct6在雌性耳蜗中表达更高，且MCT6过表达在暴露于N-乙酰-L-半胱氨酸-顺铂而非顺铂后增加细胞铂蓄积。结论：总之，这些发现确定MCT6是通过选择性转运毒性铂代谢物来性别依赖性调节顺铂耳毒性的调节因子。意义声明：本研究确定MCT6（SLC16A5）通过介导毒性顺铂代谢物的耳蜗转运而成为顺铂耳毒性的性别依赖性调节因子，揭示了一种在不改变全身铂暴露的情况下降低毒性的新机制。
英文摘要
Cisplatin is a widely used anticancer drug, but up to 75% of patients develop ototoxicity, for which there are no fully effective preventive or curative therapies. Although genetic variation in the monocarboxylate transporter 6 (MCT6; SLC16A5) has been associated with reduced cisplatin-induced hearing loss, these findings have not been consistently replicated, and the underlying mechanism has remained unclear. We hypothesized that MCT6 mediates uptake of a cytotoxic cisplatin metabolite and that loss of MCT6 confers protection from cisplatin-induced ototoxicity. Here we show that MCT6 selectively mediates uptake of the cisplatin metabolite N-acetyl-L-cysteine-cisplatin and drives sex-dependent ototoxicity in vivo. Using genetic, pharmacokinetic, and functional auditory approaches, we demonstrate that Mct6 deficiency does not alter systemic platinum exposure but provides robust protection from cisplatin-induced hearing loss in female, but not male, mice. Consistent with this phenotype, Mct6 expression is higher in female cochleae, and MCT6 overexpression increases cellular platinum accumulation following exposure to N-acetyl-L-cysteine-cisplatin but not cisplatin. Together, these findings identify MCT6 as a sex-dependent regulator of cisplatin ototoxicity through selective transport of a toxic platinum metabolite. SIGNIFICANCE STATEMENT: This study identifies MCT6 (SLC16A5) as a sex-dependent regulator of cisplatin ototoxicity by mediating cochlear transport of a toxic cisplatin metabolite, revealing a novel mechanism to reduce toxicity without altering systemic platinum exposure.