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Aop: 276

AOP Title

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Inhibition of complex I of the electron transport chain leading to chemical induced Fanconi syndrome

Short name:

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Complex I inhibition leads to Fanconi syndrome

Graphical Representation

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Authors

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Paul Jennings, Alice Limonciel

Point of Contact

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Marvin Martens   (email point of contact)

Contributors

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  • Marvin Martens

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on January 29, 2019 08:44

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Revision dates for related pages

Page Revision Date/Time
Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) March 28, 2018 04:51
Inhibition, NADH-ubiquinone oxidoreductase (complex I) March 12, 2018 11:03
Decrease, Oxidative phosphorylation December 20, 2018 10:16
Decreased Na/K ATPase activity December 20, 2018 10:18
Decreased proximal tubular vectorial transport December 20, 2018 10:20
Chemical induced Fanconi syndrome December 20, 2018 10:24
Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) leads to Inhibition, NADH-ubiquinone oxidoreductase (complex I) August 25, 2017 09:35
Inhibition, NADH-ubiquinone oxidoreductase (complex I) leads to Decrease, OXPHOS December 20, 2018 10:27
Decrease, OXPHOS leads to Decreased Na/K ATPase activity December 20, 2018 10:30
Decreased Na/K ATPase activity leads to Decreased proximal tubular vectorial transport December 20, 2018 10:32
Decreased proximal tubular vectorial transport leads to Chemical induced Fanconi syndrome December 20, 2018 10:39

Abstract

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This AOP describes how inhibitors of complex I of the mitochondrial electron transport chain (ETC) can affect proximal tubule vectorial transport. This can lead to Fanconi syndrome (FS) as an adverse outcome, via a depletion of ATP leading to decreased vectorial transport. Indeed, chemicals that target complex I cause a large disturbance in the supply of electrons to the ETC, resulting in decreased efficiency of mitochondrial respiration. Since this process is responsible for the production of most of the ATP in mammalian cells, this likely results in an impairment of transport by ATP-dependent transporters such as the sodium/potassium ATPase. This leads to a decrease in downstream secondary active transports of water and solutes, which is the main characteristic of FS. The primary organism targeted with this AOP is humans, with potential applicability to other mammalian species. Vrije Universit is working in EU-ToxRisk case study 4 and the renal exploratory study on addressing data gaps, in particular, to produce data to be used in modeling of a quantitative AOP.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 888 Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I)
2 KE 887 Inhibition, NADH-ubiquinone oxidoreductase (complex I) Inhibition, NADH-ubiquinone oxidoreductase (complex I)
3 KE 1477 Decrease, Oxidative phosphorylation Decrease, OXPHOS
4 KE 1562 Decreased Na/K ATPase activity Decreased Na/K ATPase activity
5 KE 1563 Decreased proximal tubular vectorial transport Decreased proximal tubular vectorial transport
6 AO 1564 Chemical induced Fanconi syndrome Chemical induced Fanconi syndrome

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) leads to Inhibition, NADH-ubiquinone oxidoreductase (complex I) adjacent Not Specified Not Specified
Inhibition, NADH-ubiquinone oxidoreductase (complex I) leads to Decrease, OXPHOS adjacent Not Specified Not Specified
Decrease, OXPHOS leads to Decreased Na/K ATPase activity adjacent Not Specified Not Specified
Decreased Na/K ATPase activity leads to Decreased proximal tubular vectorial transport adjacent Not Specified Not Specified
Decreased proximal tubular vectorial transport leads to Chemical induced Fanconi syndrome adjacent Not Specified Not Specified

Network View

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Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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