title: Macrophage-Mediated Clofazimine Sequestration Is Accompanied by a Shift in Host Energy Metabolism.
abstract: 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 using1H-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.
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109; NMR Metabolomics Laboratory, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Julie
authors.initials: J
authors.lastname: Trexel
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Gi S
authors.initials: GS
authors.lastname: Yoon
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Rahul K
authors.initials: RK
authors.lastname: Keswani
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109; NMR Metabolomics Laboratory, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Cora
authors.initials: C
authors.lastname: McHugh
authors.affiliation: NMR Metabolomics Laboratory, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Larisa
authors.initials: L
authors.lastname: Yeomans
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Victor
authors.initials: V
authors.lastname: Vitvitsky
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Sudha
authors.initials: S
authors.lastname: Sud
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109; NMR Metabolomics Laboratory, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Gus R
authors.initials: GR
authors.lastname: Rosania
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109; NMR Metabolomics Laboratory, University of Michigan, Ann Arbor, Michigan 48109; Center for Computational Medicine and Bioinformatics, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109. Electronic address: stringek@umich.edu.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Stringer
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology; D002991:Clofazimine / Q000008:administration & dosage* / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000893:Anti-Inflammatory Agents; D002991:Clofazimine
keywords: granulomas; intracellular drug crystals; metabolomics; microbiome; nuclear magnetic resonance; pharmacodynamics; pharmacometabolomics