中国药物警戒 ›› 2026, Vol. 23 ›› Issue (8): 841-847.
DOI: 10.19803/j.1672-8629.20260087

• 基础与临床研究 • 上一篇    下一篇

伊布莫仑体外致突变性风险研究

叶倩1,2, 寇小旋1,2,Δ, 牛茜怡1,2, 宋捷1,2, 李晓瑜3#, 文海若1,2,*   

  1. 1中国食品药品检定研究院安全评价研究所,北京 100176;
    2药品监管科学全国重点实验室,北京 102629;
    3重庆大学机械与运载工程学院,重庆 400030
  • 收稿日期:2026-01-29 出版日期:2026-08-15 发布日期:2026-08-17
  • 通讯作者: *文海若,女,博士,研究员,遗传毒理学。E-mail: wenhairuo@nifdc.org.cn#为共同通信作者。
  • 作者简介:叶倩,女,硕士,遗传毒理学。△为并列第一作者。
  • 基金资助:
    国家自然科学基金资助项目（82473889）; 药品监管科学全国重点实验室课题“药品杂质遗传毒性评价新技术和生物标志物研究”（2023SKLDRS0128）

In vitro mutagenic risk of ibutamoren

Ye Qian1,2, Kou Xiaoxuan1,2,Δ, Niu Qianyi1,2, Song Jie1,2, Li Xiaoyu3#, Wen Hairuo1,2,*   

  1. 1Institute of Safety Evaluation, National Institutes for Food and Drug Control, Beijing 100176, China;
    2State Key Laboratory of Drug Regulatory Science, Beijing 102629, China;
    3College of Mechanical and Vehicle Engineering, Chongqing University, Chongqing 400030, China
  • Received:2026-01-29 Online:2026-08-15 Published:2026-08-17

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摘要： 目的 使用多种遗传毒性试验评价伊布莫仑的体外致突变性风险。方法 采用定量构效关系计算机模型技术（Derek和Sarah模型）预测伊布莫仑的遗传毒性,进一步采用细菌回复突变试验、小鼠淋巴瘤基因突变试验（MLA）和PIG-A基因突变试验进行验证。使用5种菌株分别与伊布莫仑在有/无代谢活化系统混合液中进行试验。使用L5178Y细胞与伊布莫仑在3种处理条件（+S9/3 h、-S9/3 h、-S9/24 h）下进行MLA试验。TK6细胞分别与系列浓度（25、50、75、100、150 μg·mL-1）伊布莫仑作用4 h（+S9）,计算细胞相对倍增速率（RPD）评价受试物细胞毒性,并检测突变细胞（CD55-CD59-/CD19+）发生率。结果 伊布莫仑在非S9和大鼠肝S9代谢活化条件下对TA98有致突变作用;在3种处理条件（+S9/3 h、-S9/3 h、-S9/24 h）下,对L5178Y细胞无致突变性;与溶媒对照组相比,150 μg·mL-1伊布莫仑在2%S9代谢活化条件下,PIG-A基因突变率显著升高（P<0.001）,且有剂量相关性。结论 伊布莫仑的代谢产物之一苯甲醛可能是其有致突变性的原因之一,其具体致突变性机制仍需进一步研究证实。

关键词: 伊布莫仑, 生长激素分泌激素受体激动剂, 致突变性风险, 细菌回复突变试验, 小鼠淋巴瘤基因突变试验, 体外PIG-A基因突变试验, 构效分析, 小鼠

Abstract: Objective To evaluate the in vitro mutagenic risk of ibutamoren using multiple genotoxicity assays. Methods The genotoxic potential of ibutamoren was estimated via computer modeling based on quantitative structure-activity relationships (Dereck and Sarah models) before being validated via bacterial reverse mutation assays, mice lymphoma gene mutation assay, and PIG-A gene mutation assay. Five bacterial strains were tested in the presence or absence of a metabolic activation system that contained ibutamoren. MLA assays were performed using L5178Y cells and ibutamoren under three treatment conditions (+S9/3 h, -S9/3 h, -S9/24 h). The relative proliferation rate (RPD) was calculated for TK6 cells exposed to ibutamoren at different concentrations for 4 hours (+S9) to assess cytotoxicity, and the incidence of mutant cells (CD55-CD59-/CD19+) was detected. Results Ibutamoren was mutagenic to TA98 cells in the absence of S9 and under metabolic activation by rat liver S9, but not to L5178Y cells under any of the three treatment conditions (+S9/3 h, -S9/3 h,-S9/24 h). Compared to the solvent control group, ibutamoren at 150 μg·mL-1 significantly increased PIG-A gene mutation under metabolic activation by 2%S9 (P<0.001) in a dose-dependent manner. Conclusion Benzaldehyde, a metabolite of ibutamoren, can possibly be a contributor to its mutagenicity, but the precise mechanism needs to be investigated.

Key words: Ibutamoren, Ghrelin Receptor (GHSR1a) Agonist, Mutagenic Risk, Bacterial Reverse Mutation Assay, Mouse Lymphoma Assay (MLA), In vitro PIG-A Gene Mutation Assay, Structure-Activity Analysis, Mice

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