Morita Koji, Iigo Toru, Jimbo Kaho, Jimbo Akihiro, Suzuki Takashi, Edo Naoki, Yamazaki Hiroki, Uno Kenji, Tsukamoto Kazuhisa, Ishikawa Toshio
Division of Endocrinology and Metabolism, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, JPN.
Cureus. 2025 Aug 10;17(8):e89750. doi: 10.7759/cureus.89750. eCollection 2025 Aug.
Roxadustat, a drug recently approved for treating renal anemia, might activate thyroid hormone receptors (TRα and TRβ). We, thus, investigated the direct effects of roxadustat on intact TRα and TRβ in vitro. U2OS, MCF-7, COS-7, and Caco-2 cells were transiently transfected with a firefly luciferase reporter plasmid highly responsive to the activation of TRα and TRβ, along with a plasmid overexpressing either TRα or TRβ. Transfected cells were incubated for three hours in 100% thyroid hormone-stripped fetal bovine serum (FBS) with or without either roxadustat or triiodothyronine (T3). Also, transfected U2OS cells were placed for three hours in 100% unprocessed normal adult human serum with or without the addition of either roxadustat or T3. Cell lysates were measured for firefly luciferase activity. Roxadustat induced firefly luciferase activities when added at clinically achievable serum concentrations in TRα- or TRβ-transfected U2OS, MCF-7, COS-7, and Caco-2 cells placed in thyroid hormone-deprived FBS. The induction was comparable to or greater than that observed with T3 added at normal or even supranormal serum concentrations. Roxadustat also increased firefly luciferase activities in TRα- or TRβ-transfected U2OS cells in adult human serum. These data suggest the possibility that roxadustat could activate TRα and TRβ at clinically relevant concentrations. Physicians prescribing roxadustat should be aware of its thyromimetic activity.
罗沙司他是一种最近被批准用于治疗肾性贫血的药物，它可能会激活甲状腺激素受体（TRα和TRβ）。因此，我们在体外研究了罗沙司他对完整的TRα和TRβ的直接作用。将U2OS、MCF-7、COS-7和Caco-2细胞用对TRα和TRβ激活高度敏感的萤火虫荧光素酶报告质粒进行瞬时转染，并转染一个过表达TRα或TRβ的质粒。将转染后的细胞在100%去除甲状腺激素的胎牛血清（FBS）中孵育三小时，添加或不添加罗沙司他或三碘甲状腺原氨酸（T3）。此外，将转染后的U2OS细胞在100%未处理的正常成人血清中放置三小时，添加或不添加罗沙司他或T3。测量细胞裂解物中的萤火虫荧光素酶活性。当在置于缺乏甲状腺激素的FBS中的TRα或TRβ转染的U2OS、MCF-7、COS-7和Caco-2细胞中，以临床可达到的血清浓度添加罗沙司他时，它会诱导萤火虫荧光素酶活性。这种诱导作用与在正常甚至超正常血清浓度下添加T3时观察到的作用相当或更强。罗沙司他在成人血清中也增加了TRα或TRβ转染的U2OS细胞中的萤火虫荧光素酶活性。这些数据表明罗沙司他在临床相关浓度下可能激活TRα和TRβ的可能性。开具罗沙司他处方的医生应注意其拟甲状腺活性。
