Antioxidant effect of ascorbic acid against cisplatin-induced nephrotoxicity and P-glycoprotein expression in rats.
Antioxidant effect of ascorbic acid against cisplatin-induced nephrotoxicity and P-glycoprotein expression in rats.
复制标题
抗坏血酸对顺铂诱导的大鼠肾毒性和 P-糖蛋白表达的抗氧化作用。
DOI：
10.1016/j.ejphar.2021.174395
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Kobayashi M.
中科院分区：
文献类型：
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作者：
Okamoto K;Kitaichi F;Saito Y;Ueda H;Narumi K;Furugen A;Kobayashi M.
顺铂 (CDDP) 是一种高效抗癌药物，广泛用于治疗多种癌症。 CDDP 诱导的肾毒性 (CIN) 是最显着的不良反应之一，氧化应激被认为是 CIN 的潜在机制之一。尽管有一些关于单次 CDDP 剂量后肾脏转运蛋白表达变化的研究，但没有报道多次 CDDP 剂量给药后肾脏转运蛋白表达的变化。据报道，P-糖蛋白（P-gp）是一种转运蛋白，由氧化应激诱导。抗坏血酸是一种具有抗氧化潜力的维生素，因此可能调节 P-gp 转运蛋白的表达并影响 CIN。在本研究中，我们的目的是评估多次 CDDP 剂量给药后几种肾脏转运蛋白表达的变异性以及抗坏血酸对转运蛋白表达和 CIN 的抗氧化作用。多剂量的 CDDP 会影响肾损伤标志物和肾脏中的抗氧化剂。此外，CDDP 还上调了 P-gp、乳腺癌耐药蛋白和多药耐药相关蛋白 4 的表达。使用正常肾细胞系，我们证明抗坏血酸因其高超氧化物清除能力而减弱 CDDP 诱导的细胞毒性。 CDDP 和抗坏血酸每周一次注射给大鼠，持续三周，观察到抗坏血酸的联合给药可减弱 CIN 并调节抗氧化标志物。此外，抗坏血酸降低了 P-gp 的表达，而 CDDP 则上调了 P-gp 的表达。总之，抗坏血酸可以减弱 CIN 并逆转 P-gp 介导的药物药代动力学变化。
Cisplatin (CDDP) is a highly potent anticancer drug that is widely used in the treatment of several cancers. CDDP-induced nephrotoxicity (CIN) is one of the most significant adverse effects, and oxidative stress is thought to be one of the mechanisms underlying CIN. Although there are some studies available on the variability in transporter expression in the kidney after a single CDDP dose, none have reported the change in renal transporter expression after multiple CDDP dose administrations. P-glycoprotein (P-gp), a transporter, is reported to be induced by oxidative stress. Ascorbic acid is a vitamin with antioxidant potential and therefore, may regulate the expression of P-gp transporter and affect CIN. In the present study, our aim was to assess the variability in expression of several renal transporters after multiple CDDP dose administrations and the antioxidant effect of ascorbic acid against transporter expression and CIN. Multiple doses of CDDP affected markers of kidney injury and antioxidants in the kidneys. Also, the expression of P-gp, breast cancer resistance protein, and multidrug resistance-associated protein 4 was upregulated by CDDP. Using a normal kidney cell line, we demonstrated that ascorbic acid attenuated CDDP-induced cytotoxicity due to its high superoxide scavenging ability. CDDP and ascorbic acid were injected into rats once a week for three weeks, and it was observed that co-administration of ascorbic acid attenuated CIN and regulated antioxidant marker. In addition, ascorbic acid reduced P-gp expression, which was upregulated by CDDP. In conclusion, ascorbic acid may attenuate CIN and reverse P-gp-mediated changes in drug pharmacokinetics.