Blood donor exposome and impact of common drugs on red blood cell metabolism
Blood donor exposome and impact of common drugs on red blood cell metabolism
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DOI：
10.1172/jci.insight.146175
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发表时间：
2021-02-08
期刊：
影响因子：
8
通讯作者：
D'Alessandro, Angelo
中科院分区：
文献类型：
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作者：
Nemkov, Travis;Stefanoni, Davide;D'Alessandro, Angelo
基于最近红细胞蛋白质组图谱的计算模型表明，成熟的红细胞可能含有常见药物的靶标。这一预测与血库中的红细胞储存有关，其中源自饮食、医源性或环境暴露（“暴露组”）的小分子药物或其他异种代谢物的影响可能会改变红细胞能量和氧化还原代谢，从而影响红细胞储存质量和输血后功效。为了测试这一预测，我们在这里提供了献血者暴露组的全面表征，包括在接受者流行病学和献者评估研究 Ill 红细胞遗漏 (REDS-Ill RBC-Omics) 研究中检测 250 名健康志愿者捐赠的血液单位中的常见处方药和非处方药。基于对 FDA 批准的 1366 种药物的高通量药物筛选，我们报告约 65% 的测试药物对红细胞代谢有影响。使用代谢物作为预测因子构建的机器学习模型能够准确预测多种药物类别/靶点的药物（双磷酸盐、抗胆碱能药物、钙通道阻滞剂、肾上腺素能药物、质子泵抑制剂、抗代谢物、选择性血清素再摄取抑制剂和 mTOR），表明这些药物对红细胞代谢具有直接、保守和实质性的影响。作为原理证明，我们在此证明抗酸雷尼替丁（尽管在献血者群体中很少检测到）对体外储存质量的红细胞标记物具有强烈影响。因此，我们表明，用雷尼替丁补充储存在袋中的血液单位可以 - 通过涉及 1-磷酸鞘氨醇依赖的红细胞糖酵解调节和/或直接与血红蛋白结合的机制 - 改善红细胞代谢和储存质量。
Computational models based on recent maps of the RBC proteome suggest that mature erythrocytes may harbor targets for common drugs. This prediction is relevant to RBC storage in the blood bank, in which the impact of small molecule drugs or other xenometabolites deriving from dietary, iatrogenic, or environmental exposures ("exposome") may alter erythrocyte energy and redox metabolism and, in so doing, affect red cell storage quality and posttransfusion efficacy. To test this prediction, here we provide a comprehensive characterization of the blood donor exposome, including the detection of common prescription and over-the-counter drugs in blood units donated by 250 healthy volunteers in the Recipient Epidemiology and Donor Evaluation Study Ill Red Blood Cell-Omits (REDS-Ill RBC-Omics) Study. Based on high-throughput drug screenings of 1366 FDA-approved drugs, we report that approximately 65% of the tested drugs had an impact on erythrocyte metabolism. Machine learning models built using metabolites as predictors were able to accurately predict drugs for several drug classes/targets (bisphosphonates, anticholinergics, calcium channel blockers, adrenergics, proton pump inhibitors, antimetabolites, selective serotonin reuptake inhibitors, and mTOR), suggesting that these drugs have a direct, conserved, and substantial impact on erythrocyte metabolism. As a proof of principle, here we show that the antacid ranitidine - though rarely detected in the blood donor population - has a strong effect on RBC markers of storage quality in vitro. We thus show that supplementation of blood units stored in bags with ranitidine could - through mechanisms involving sphingosine 1-phosphate-dependent modulation of erythrocyte glycolys is and/or direct binding to hemoglobin - improve erythrocyte metabolism and storage quality.