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Event: 877

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Inhibition, organic anion transporter 1 (OAT1)

Short name

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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

Organ term
proximal tubule

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
signaling	solute carrier family 22 member 6	decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
OAT1 inhibition	MolecularInitiatingEvent	Kellie Fay (send email)	Under Development: Contributions and Comments Welcome

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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).

Domain of Applicability

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References

List of the literature that was cited for this KE description. More help

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.