Macrophage-Mediated Clofazimine Sequestration Is Accompanied by a Shift in Host Energy Metabolism
| Autor: | Gi Sang Yoon, Cora McHugh, Yihan Sun, Gus R. Rosania, Victor Vitvitsky, Rahul K. Keswani, Sudha Sud, Larisa Yeomans, Kathleen A. Stringer, Julie Trexel, Ruma Banerjee |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.drug_class Metabolite Anti-Inflammatory Agents Pharmaceutical Science Pharmacology Biology Clofazimine Article Energy homeostasis Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Macrophage Glycolysis Macrophages Metabolism Receptor antagonist Mice Inbred C57BL 030104 developmental biology chemistry 030220 oncology & carcinogenesis Energy Metabolism Intracellular medicine.drug |
| Zdroj: | Journal of Pharmaceutical Sciences. 106:1162-1174 |
| ISSN: | 0022-3549 |
| DOI: | 10.1016/j.xphs.2016.12.009 |
| Popis: | Prolonged (8 weeks) oral administration of clofazimine results in a profound pharmacodynamic response—bioaccumulation in macrophages (including Kupffer cells) as intracellular crystal-like drug inclusions (CLDIs) with an associated increase in interleukin-1 receptor antagonist production. Notably, CLDI formation in Kupffer cells concomitantly occurs with the formation of macrophage-centric granulomas. Accordingly, we sought to understand the impact of these events on host metabolism using 1 H-nuclear magnetic resonance metabolomics. Mice received a clofazimine or vehicle-enriched (sham) diet for at least 8 weeks. At 2 weeks, the antimicrobial activity of clofazimine was evident by changes in urine metabolites. From 2 to 8 weeks, there was a striking change in metabolite levels indicative of a reorientation of host energy metabolism paralleling the onset of CLDI and granuloma formation. This was evidenced by a progressive reduction in urine levels of metabolites involved in one-carbon metabolism with corresponding increases in whole blood, and changes in metabolites associated with lipid, nucleotide and amino acid metabolism, and glycolysis. Although clofazimine-fed mice ate more, they gained less weight than control mice. Together, these results indicate that macrophage sequestration of clofazimine as CLDIs and granuloma formation is accompanied by a profound metabolic disruption in energy homeostasis and one-carbon metabolism. |
| Databáze: | OpenAIRE |
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