Multiscale Distribution and Bioaccumulation Analysis of Clofazimine Reveals a Massive Immune System-Mediated Xenobiotic Sequestration Response
Multiscale Distribution and Bioaccumulation Analysis of Clofazimine Reveals a Massive Immune System-Mediated Xenobiotic Sequestration Response
复制标题
DOI：
10.1128/aac.01731-12
复制
发表时间：
2013-03-01
影响因子：
4.9
通讯作者：
Rosania, Gus R.
中科院分区：
文献类型：
--
作者：
Baik, Jason;Stringer, Kathleen A.;Rosania, Gus R.
长期接触一些吸收良好但消除缓慢的外源性物质可导致其在生物体内的生物累积。在这里，我们研究了用于治疗分枝杆菌感染的riminophenazine抗生素氯法齐明的生物蓄积和分布。使用小鼠作为模型生物，我们进行了多尺度，定量分析，以揭示慢性，长期暴露过程中的氯法齐明生物蓄积的网站。值得注意的是，在饮食给药的3至8周之间，氯法齐明大量地从脂肪组织重新分布到肝脏和脾脏。在此期间，脂肪和血清中的氯法齐明浓度显著降低，而脾脏和肝脏中的氯法齐明质量增加>10倍。这些变化被氯法齐明在淋巴器官的常驻巨噬细胞中的蓄积所掩盖，脾脏中多达90%的氯法齐明质量被隔离在细胞内晶体样药物包涵体（CLDIs）中。与肝和脾巨噬细胞的CLDI相关的氯法齐明的量不成比例地增加，并最终占宿主中总氯法齐明的主要部分。停药后，氯法齐明保留在脾脏中，而其在血液和其他器官中的浓度降低。在免疫学上，氯法齐明生物蓄积诱导局部单核细胞特异性上调各种趋化因子和受体。然而，白细胞介素-1受体拮抗剂也上调，急性期反应途径和氧化能力降低或保持不变，标志着抗炎反应的伴随激活。这些实验表明，诱导型，免疫系统依赖性，异生素螯合反应影响的小分子化疗剂的非典型药代动力学。
Chronic exposure to some well-absorbed but slowly eliminated xenobiotics can lead to their bioaccumulation in living organisms. Here, we studied the bioaccumulation and distribution of clofazimine, a riminophenazine antibiotic used to treat mycobacterial infection. Using mice as a model organism, we performed a multiscale, quantitative analysis to reveal the sites of clofazimine bioaccumulation during chronic, long-term exposure. Remarkably, between 3 and 8 weeks of dietary administration, clofazimine massively redistributed from adipose tissue to liver and spleen. During this time, clofazimine concentration in fat and serum significantly decreased, while the mass of clofazimine in spleen and liver increased by >10-fold. These changes were paralleled by the accumulation of clofazimine in the resident macrophages of the lymphatic organs, with as much as 90% of the clofazimine mass in spleen sequestered in intracellular crystal-like drug inclusions (CLDIs). The amount of clofazimine associated with CLDIs of liver and spleen macrophages disproportionately increased and ultimately accounted for a major fraction of the total clofazimine in the host. After treatment was discontinued, clofazimine was retained in spleen while its concentrations decreased in blood and other organs. Immunologically, clofazimine bioaccumulation induced a local, monocyte-specific upregulation of various chemokines and receptors. However, interleukin-1 receptor antagonist was also upregulated, and the acute-phase response pathways and oxidant capacity decreased or remained unchanged, marking a concomitant activation of an anti-inflammatory response. These experiments indicate an inducible, immune system-dependent, xenobiotic sequestration response affecting the atypical pharmacokinetics of a small molecule chemotherapeutic agent.