Effects of indole and indoxyl on the intracellular oxidation level and phagocytic activity of differentiated HL-60 human macrophage cells

J Toxicol Sci. 2020;45(9):569-579. doi: 10.2131/jts.45.569.

Abstract

Indoxyl, a derivative of indole originating from tryptophan, may undergo phase-II sulfate-conjugation pathway, thereby forming indoxyl sulfate (IS) in vivo. We previously reported that IS, a well-known uremic toxin, can increase the intracellular oxidation level and decrease the phagocytic activity in a differentiated HL-60 human macrophage cell model. Using the same cell model, the current study aimed to investigate whether indole and indoxyl (the metabolic precursors of indoxyl and IS, respectively) may cause macrophage immune dysfunction. Results obtained indicated that intracellular oxidation level and cytotoxicity markedly increased upon treatment with indole and indoxyl, in comparison with IS. Incubation of the cells with indole and indoxyl also resulted in attenuated phagocytic activity. Human serum albumin (HSA)-binding assay confirmed that tryptophan and IS, but not indole and indoxyl, could selectively bind to the site II in HSA. Collectively, the results indicated that indole and indoxyl may strongly down-regulate the phagocytic immune function of macrophages, whereas IS, formed upon sulfate conjugation of indoxyl, may exhibit enhanced HSA-binding capability, thereby reducing the adverse effects of indoxyl.

Keywords: Indole; Indoxyl; Indoxyl sulfate; Macrophage; Oxidation; Phagocytosis.

MeSH terms

  • Cell Differentiation / drug effects
  • Cells, Cultured
  • HL-60 Cells
  • Humans
  • Indican / metabolism
  • Indoles / adverse effects*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / metabolism*
  • Oxidation-Reduction / drug effects*
  • Phagocytosis / drug effects*
  • Phagocytosis / immunology*
  • Protein Binding
  • Serum Albumin / metabolism
  • Tryptophan / metabolism

Substances

  • Indoles
  • Serum Albumin
  • indoxyl
  • indole
  • Tryptophan
  • Indican