Indoxyl Sulfate Upregulates Liver P-Glycoprotein Expression and Activity through Aryl Hydrocarbon Receptor Signaling

J Am Soc Nephrol. 2018 Mar;29(3):906-918. doi: 10.1681/ASN.2017030361. Epub 2017 Dec 8.

Abstract

In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1, SLC22A1, SLC22A7, SLC47A1, SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCB11, ABCC2, ABCC3, ABCC4, ABCC6, and ABCG2 We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters. This effect depended on the aryl hydrocarbon receptor pathway. Presence of human albumin at physiologic concentration in the culture medium did not abolish the effect of IS. In two mouse models of CKD, the decline in renal function associated with the accumulation of IS in serum and the specific upregulation of Abcb1a in the liver. Additionally, among 109 heart or kidney transplant recipients with CKD, those with higher serum levels of IS needed higher doses of cyclosporin, a P-gp substrate, to obtain the cyclosporin target blood concentration. This need associated with serum levels of IS independent of renal function. These findings suggest that increased activity of P-gp could be responsible for increased hepatic cyclosporin clearance. Altogether, these results suggest that uremic toxins, such as IS, through effects on drug transporters, may modify the nonrenal clearance of drugs in patients with CKD.

Keywords: ABC transporter; chronic kidney disease; cyclosporine; drug transporter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • Albumins / pharmacology
  • Animals
  • Cyclosporine / blood
  • Cyclosporine / pharmacokinetics
  • Disease Models, Animal
  • Female
  • Gene Expression / drug effects
  • Heart Transplantation
  • Hep G2 Cells
  • Humans
  • Immunosuppressive Agents / blood
  • Immunosuppressive Agents / pharmacokinetics
  • Indican / blood*
  • Indican / pharmacology
  • Kidney Transplantation
  • Liver / metabolism
  • Male
  • Mice
  • Middle Aged
  • Multidrug Resistance-Associated Protein 2
  • RNA, Messenger / metabolism
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Renal Insufficiency, Chronic / blood*
  • Renal Insufficiency, Chronic / physiopathology
  • Signal Transduction
  • Up-Regulation

Substances

  • ABCB1 protein, human
  • ABCC2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Albumins
  • Immunosuppressive Agents
  • Multidrug Resistance-Associated Protein 2
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon
  • Cyclosporine
  • multidrug resistance protein 3
  • Indican