Department of Bioengineering and Therapeutic Sciences, University of California at San Francisco, San Francisco, California, 94158, USA.
College of Medicine, SUNY Downstate Health Sciences University, Brooklyn, New York, 11203, USA.
AAPS J. 2021 Mar 1;23(2):35. doi: 10.1208/s12248-021-00562-4.
A rare cause of megaloblastic anemia (MA) is thiamine-responsive megaloblastic anemia (TRMA), a genetic disorder caused by mutations in SLC19A2 (encoding THTR1), a thiamine transporter. The study objectives were to (1) functionally characterize selected TRMA-associated SLC19A2 variants and (2) determine whether current prescription drugs associated with drug-induced MA (DIMA) may act via inhibition of SLC19A2. Functional characterization of selected SLC19A2 variants was performed by confocal microscopy and isotopic uptake studies of [3H]-thiamine in HEK293 cells. Sixty-three drugs associated with DIMA were screened for SLC19A2 inhibition in isotopic uptake studies. Three previously uncharacterized SLC19A2 variants identified in TRMA patients exhibited disrupted localization to the plasma membrane along with near-complete loss-of-function. Ten of 63 drugs inhibited SLC19A2-mediated thiamine transport ≥ 50% at screening concentrations; however, with the exception of erythromycin, none was predicted to inhibit SLC19A2 at clinically relevant unbound plasma concentrations. Data from electronic health records revealed reduced levels of thiamine pyrophosphate (TPP) in patients prescribed erythromycin, consistent with inhibition of SLC19A2-mediated thiamine transport. Here, we confirmed the role of three SLC19A2 variants in TRMA pathology. Additionally, we report that inhibition of SLC19A2 is a potential, but uncommon mechanism for DIMA.
巨幼细胞性贫血（MA）的一个罕见病因是硫胺素反应性巨幼细胞性贫血（TRMA），这是一种由 SLC19A2（编码 THTR1，一种硫胺素转运蛋白）突变引起的遗传性疾病。本研究的目的是：（1）对选定的 TRMA 相关 SLC19A2 变体进行功能表征；（2）确定目前与药物诱导性 MA（DIMA）相关的处方药物是否可能通过抑制 SLC19A2 起作用。通过共聚焦显微镜和 HEK293 细胞中 [3H]-硫胺素的同位素摄取研究对选定的 SLC19A2 变体进行功能表征。在同位素摄取研究中筛选了 63 种与 DIMA 相关的药物，以确定其对 SLC19A2 的抑制作用。在 TRMA 患者中鉴定出的三个以前未表征的 SLC19A2 变体表现出定位到质膜的缺陷，同时几乎完全丧失功能。在筛选浓度下，有 10 种药物抑制 SLC19A2 介导的硫胺素转运≥50%；然而，除了红霉素之外，在临床相关的未结合血浆浓度下，没有一种药物被预测会抑制 SLC19A2。电子健康记录的数据显示，服用红霉素的患者体内硫胺素焦磷酸盐（TPP）水平降低，与 SLC19A2 介导的硫胺素转运抑制一致。在这里，我们证实了三个 SLC19A2 变体在 TRMA 病理中的作用。此外，我们报告 SLC19A2 的抑制是 DIMA 的一种潜在但不常见的机制。
