Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Toxicol Appl Pharmacol. 2022 Aug 15;449:116140. doi: 10.1016/j.taap.2022.116140. Epub 2022 Jun 23.
The unpredictable pharmacokinetics of non-renal cleared drugs in chronic kidney disease (CKD) patients is associated with the activity of drug transporters. However, the mechanisms underlying regulation of drug transporters are yet to be established. In this study, we demonstrated the involvement of a HDAC2-Foxo3α pathway in advanced oxidation protein products (AOPPs)-induced ATP-binding cassette subfamily B member 1 (ABCB1) expression and activity. The correlation of AOPPs accumulation with concentration of cyclosporine in plasma was evaluated in 194 patients with transplantation. Molecular changes in acetylation of various histones and related regulatory molecules were examined in HepG2 cell cultures treated with AOPPs. Accumulation of AOPPs in serum in relation to molecular changes in HDAC2-Foxo3α in vivo were evaluated in 5/6 nephrectomy (5/6 nx) and oral adenine (Adenine) CKD rat models. Interestingly, the cyclosporine level was negatively correlated with AOPPs in plasma. In addition, AOPPs markedly suppressed the expression of histone deacetylase 2 (HDAC2), inducing ABCB1 expression and activity in vitro and in vivo. Importantly, AOPPs modulated phosphorylation of Foxo3α and the upstream Akt protein. Our findings indicate that AOPPs regulate the expression and activity of ABCB1 via reducing HDAC2 expression and activating Foxo3α-dependent signaling. The collective results support the utility of AOPPs as a potential target for drug and/or dosage adjustment in CKD patients. Targeting of AOPPs presents a novel approach to regulate non-renal clearance.
在慢性肾脏病（CKD）患者中，非肾清除药物的不可预测药代动力学与药物转运体的活性有关。然而，药物转运体调节的机制尚未确定。在这项研究中，我们证明了 HDAC2-Foxo3α 途径在晚期氧化蛋白产物（AOPPs）诱导的 ATP 结合盒亚家族 B 成员 1（ABCB1）表达和活性中的作用。在 194 名接受移植的患者中评估了 AOPPs 积累与血浆中环孢素浓度的相关性。在 AOPPs 处理的 HepG2 细胞培养物中检查了各种组蛋白和相关调节分子乙酰化的分子变化。在 5/6 肾切除术（5/6 nx）和口服腺嘌呤（Adenine）CKD 大鼠模型中评估了体内 HDAC2-Foxo3α 相关 AOPPs 积累与分子变化的关系。有趣的是，环孢素水平与血浆中的 AOPPs 呈负相关。此外，AOPPs 明显抑制组蛋白去乙酰化酶 2（HDAC2）的表达，在体外和体内诱导 ABCB1 的表达和活性。重要的是，AOPPs 调节 Foxo3α 和上游 Akt 蛋白的磷酸化。我们的研究结果表明，AOPPs 通过降低 HDAC2 的表达和激活 Foxo3α 依赖性信号来调节 ABCB1 的表达和活性。总的来说，结果支持 AOPPs 作为 CKD 患者药物和/或剂量调整的潜在靶点。靶向 AOPPs 提供了一种调节非肾清除的新方法。
