Multidrug Resistance Protein 1 Deficiency Promotes Doxorubicin-Induced Ovarian Toxicity in Female Mice.
Multidrug Resistance Protein 1 Deficiency Promotes Doxorubicin-Induced Ovarian Toxicity in Female Mice.
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多药耐药蛋白 1 缺乏会促进多柔比星诱导的雌性小鼠卵巢毒性。
DOI：
10.1093/toxsci/kfy038
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Xiao,Shuo
中科院分区：
文献类型：
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作者：
Wang,Yingzheng;Liu,Mingjun;Zhang,Jiyang;Liu,Yuwen;Kopp,Megan;Zheng,Weiwei;Xiao,Shuo
多药耐药蛋白1（MDR 1）是一种将底物输出细胞的III期药物转运蛋白，在癌组织和正常组织中都有发现。癌细胞中MDR 1的过度表达导致了多药耐药，而正常组织中的MDR 1保护它们免受化学诱导的毒性。目前，MDR 1在卵巢中的作用尚未完全了解。我们的目的是确定MDR 1在预防化疗引起的卵巢毒性中的作用。本研究采用体内转基因小鼠模型和体外卵泡培养模型，研究卵巢中MDR 1的表达，MDR 1缺陷对阿霉素（DOX）所致卵巢毒性的影响，以及卵巢激素对MDR 1的调节作用。结果表明，MDR 1在卵巢上皮细胞、间质细胞、卵泡膜细胞层、内皮细胞和黄体细胞中均有表达。MDR 1的缺失并不影响雌性卵巢功能和生育能力;然而，在体内和体外模型中，MDR 1的缺失显著加重了DOX诱导的卵巢毒性。MDR 1在动情期和动情后期卵巢中的表达水平显著高于动情前期和动情间期。然而，这种动态表达模式不受卵巢类固醇激素雌激素（E2）和孕激素（P4）的调节，但与黄体的数量和状态相关。总之，我们的研究表明，MDR 1的缺乏促进了DOX诱导的卵巢毒性，这表明MDR 1在化疗期间保护女性卵巢功能中的关键作用。
Multidrug resistance protein 1 (MDR1), a phase III drug transporter that exports substrates out of cells, has been discovered in both cancerous and normal tissues. The over expression of MDR1 in cancer cells contributes to multiple drug resistance, whereas the MDR1 in normal tissues protects them from chemical-induced toxicity. Currently, the role of MDR1 in the ovary has not been entirely understood. Our objective is to determine the function of MDR1 in protecting against chemotherapy-induced ovarian toxicity. Using both thein vivotransgenic mouse model andin vitrofollicle culture model, we investigated the expression of MDR1 in the ovary, the effect of MDR1 deficiency on doxorubicin (DOX)-induced ovarian toxicity, and the ovarian steroid hormonal regulation of MDR1. Results showed that the MDR1 was expressed in the ovarian epithelial cells, stroma cells, theca cell layers, endothelial cells, and luteal cells. The lack of MDR1 did not affect female ovarian function and fertility; however, its deficiency significantly exacerbated the DOX-induced ovarian toxicity in bothin vivoandin vitromodels. The MDR1 showed significantly higher expression levels in the ovaries at estrus and metestrus stages than those at proestrus and diestrus stages. However, this dynamic expression pattern was not regulated by the ovarian steroid hormones of estrogen (E2) and progesterone (P4) but correlated to the number and status of corpus luteum. In conclusion, our study demonstrates that the lack of MDR1 promotes DOX-induced ovarian toxicity, suggesting the critical role of MDR1 in protecting female ovarian functions during chemotherapy.