Key Event Title
Key Event Component
|signaling||solute carrier family 22 member 6||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Organic anion transporter (OAT1) inhibition leading to renal failure and mortality||MolecularInitiatingEvent|
Level of Biological Organization
How This Key Event Works
Inhibition of the organic anion transporters (OATs) results in diminished excretion of its substrates, including uric acid. In mammals, OAT1 and OAT3 have very similar function. These take up small, hydrophilic anions from the plasma of the organism into the cytoplasm of the renal proximal tubule cells. The multi-drug resistance (MDR) transporters then transport these substrates to the lumen of the proximal convoluted tubules. Some identified substrates of OAT1 include para-aminohippurate (PAH), dicarboxylates, prostaglandins, cyclic nucleotides, urate, folate, diuretics, ACE inhibitors, antiviral agents, beta-lactam antibiotics, antineoplastics, mycotoxins, sulfate conjugates, glucuronide conjugates, cysteine conjugates, ochratoxin A, NSAIDs, and uremic toxins.
How It Is Measured or Detected
Inhibition of organic anion transporter activity may be measured by the decreased transport of a known substrate. Duan et al. (2012) measured the inhibtion of human OAT1 and OAT3 using monkey kidney COS-7 cells expressing these transporters. Inclubation with a fluorescent substrate, 6-CF, and the inhibitor at room temp for 12 min, followed by subsequent washing and lysing of the cells allowed for determination of the extent of accumulation of the 6-CF within the cells. Inhibition potency is reported as the half maximal inhibitory concentration (IC50) and may be determined from dose response curves (the concentration of inhibitor required to inhibit the maximal transporter activity by 50%) or may be estimated from the activity with and without the inhibitor (V and V0) and the concentration of the inhibitor (I): V = V0/ [1+(I/IC50)^n] where n is the slope of the relationship between uptake rate in the presence and absence of the inhibitor.
Naidoo and Swan (2009) estimated inhibition by plating chicken or vulture renal tubule cells on culture inserts, incubating with the inhibitory drug (diclofenac or meloxicam) and adding para amino hippuric acid (PAH). The net transport by the OAT was calculated as the difference between the basolateral concentration (cytoplasm) and the apical change (cytoplasm - lumen).
Evidence Supporting Taxonomic Applicability
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
1. Duan, P., et al., Potent Inhibitors of Human Organic Anion Transporters 1 and 3 from Clinical Drug Libraries: Discovery and Molecular Characterization. Molecular Pharmaceutics, 2012. 9(11): p. 3340-3346.
2. Naidoo, V. and G.E. Swan, Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 2009. 149(3): p. 269-274.
3. Sekine, T., H. Miyazaki, and H. Endou, Molecular physiology of renal organic anion transporters. American Journal of Physiology-Renal Physiology, 2006. 290(2): p. F251-F261.
4. Sekine, T., H.S. Cha, and H. Endou, The multispecific organic anion transporter (OAT) family. Pflügers Archiv. 440(3): p. 337-350.