Organic anion transporter 1 (OAT1) involved in renal cell transport of aristolochic acid I

Hum Exp Toxicol. 2012 Aug;31(8):759-70. doi: 10.1177/0960327111424302. Epub 2011 Oct 25.

Abstract

Aristolochic acids (AAs) are a family of structurally related nitrophenanthrene carboxylic acids that are present in medicinal herbs such as Aristolochia species. The organic anion transporters (OATs) of the solute carrier (SLC22) gene family located in the renal proximal tubules play a key role in the excretion of a variety of exogenous and endogenous compounds. However, it is unclear how AAs permeate into renal epithelial cells. In this regard, we investigated the role of rat OAT1 ([rOAT1] SLC22A6) in the cellular uptake of AAI in vitro and in vivo. A concentration- and time-dependent intracellular accumulation of AAI was observed in rOAT1-transfected human embryonic kidney 293 (HEK293) cells, which was 2- to 6-fold higher than the control cells. There was a significantly increased rate of cellular apoptosis in rOAT1-transfected HEK293 cells than control cells after AAI treatment. Para-aminohippuric acid (PAH) significantly reduced the intracellular accumulation of AAI in rOAT1-transfected HEK293 cells. Administration of AAI for 35 days in rats caused significantly reduced expression of OAT1 in basolateral membrane and declined renal clearance of PAH as well as renal proximal tubule injuries. These findings indicate that AAI is taken up by OAT1, which then exert its intracellular toxic effects on renal proximal tubule cells, which in turn damage functional OAT1 and may further disturb the transport of its substrates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aristolochic Acids / pharmacology*
  • Biological Transport
  • HEK293 Cells
  • Humans
  • Kidney / drug effects*
  • Kidney / metabolism
  • Male
  • Organic Anion Transport Protein 1 / metabolism*
  • Rats
  • Rats, Wistar

Substances

  • Aristolochic Acids
  • Organic Anion Transport Protein 1
  • aristolochic acid I