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AOP: 276
Title
Inhibition of complex I of the electron transport chain leading to chemical induced Fanconi syndrome
Short name
Graphical Representation
Point of Contact
Contributors
- Marvin Martens
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
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This AOP was last modified on April 29, 2023 16:03
Revision dates for related pages
Page | Revision Date/Time |
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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 | September 24, 2024 09:54 |
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
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.
AOP Development Strategy
Context
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
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MIE | 888 | Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) | Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) |
KE | 887 | Inhibition, NADH-ubiquinone oxidoreductase (complex I) | Inhibition, NADH-ubiquinone oxidoreductase (complex I) |
KE | 1477 | Decrease, Oxidative phosphorylation | Decrease, OXPHOS |
KE | 1562 | Decreased Na/K ATPase activity | Decreased Na/K ATPase activity |
KE | 1563 | Decreased proximal tubular vectorial transport | Decreased proximal tubular vectorial transport |
AO | 1564 | Chemical induced Fanconi syndrome | Chemical induced Fanconi syndrome |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
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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 |