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AOP: 130
Title
A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.
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Phospholipase A2 (LPLA2) inhibitors leading to hepatotoxicity
Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters.
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Inhibition of LPLA2, hepatotoxicity
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter.
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Handbook Version v1.0
Graphical Representation
A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs.
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Click to download graphical representation template
Explore AOP in a Third Party Tool
Additional AOP Exploration Options
Click links below to explore AOP 130, Phospholipase A2 (LPLA2) inhibitors leading to hepatotoxicity in tools offered by third parties.
Point of Contact
The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.
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Jung-Hwa Oh
(email point of contact)
Contributors
Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact.
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- Jung-Hwa Oh
- Seokjoo Yoon
Coaches
This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author.
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- Cinzia La Rocca
OECD Information Table
Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.
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| OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
|---|---|---|---|---|
| 1.39 | Under Development |
This AOP was last modified on April 02, 2024 10:03
Revision dates for related pages
| Page | Revision Date/Time |
|---|---|
| Inhibition, Phospholipase A | December 03, 2016 16:37 |
| Damage, Lipid bilayer | December 03, 2016 16:37 |
| Disturbance, Lysosomal function | September 16, 2017 10:16 |
| Occurrence, Cytoplasmic vacuolization (hepatocyte) | September 16, 2017 10:16 |
| Occurrence, Ballooning degeneration (hepatocyte) | September 16, 2017 10:16 |
| Occurrence, Cytoplasmic vacuolization (kupffer cell) | September 16, 2017 10:16 |
| Induction, Microvesicular fat | December 03, 2016 16:37 |
| Formation, Mallory body | December 03, 2016 16:37 |
| Formation, Liver fibrosis | September 16, 2017 10:16 |
| Occurrence, Cytoplasmic vacuolization (Bile duct cell) | September 16, 2017 10:16 |
| Mitochondrial dysfunction | April 17, 2024 08:26 |
| Inhibition, Phospholipase A leads to Damage, Lipid bilayer | December 03, 2016 16:38 |
| Inhibition, Phospholipase A leads to Disturbance, Lysosomal function | December 03, 2016 16:38 |
| Inhibition, Phospholipase A leads to Mitochondrial dysfunction | March 13, 2024 16:43 |
| Damage, Lipid bilayer leads to Occurrence, Cytoplasmic vacuolization (hepatocyte) | December 03, 2016 16:38 |
| Damage, Lipid bilayer leads to Occurrence, Ballooning degeneration (hepatocyte) | December 03, 2016 16:38 |
| Damage, Lipid bilayer leads to Occurrence, Cytoplasmic vacuolization (Bile duct cell) | December 03, 2016 16:38 |
| Damage, Lipid bilayer leads to Occurrence, Cytoplasmic vacuolization (kupffer cell) | December 03, 2016 16:38 |
| Disturbance, Lysosomal function leads to Occurrence, Cytoplasmic vacuolization (hepatocyte) | December 03, 2016 16:38 |
| Disturbance, Lysosomal function leads to Occurrence, Ballooning degeneration (hepatocyte) | December 03, 2016 16:38 |
| Disturbance, Lysosomal function leads to Occurrence, Cytoplasmic vacuolization (Bile duct cell) | December 03, 2016 16:38 |
| Disturbance, Lysosomal function leads to Occurrence, Cytoplasmic vacuolization (kupffer cell) | December 03, 2016 16:38 |
| Mitochondrial dysfunction leads to Occurrence, Cytoplasmic vacuolization (hepatocyte) | March 13, 2024 16:44 |
| Mitochondrial dysfunction leads to Occurrence, Ballooning degeneration (hepatocyte) | March 13, 2024 16:45 |
| Mitochondrial dysfunction leads to Occurrence, Cytoplasmic vacuolization (Bile duct cell) | March 13, 2024 16:45 |
| Mitochondrial dysfunction leads to Occurrence, Cytoplasmic vacuolization (kupffer cell) | March 13, 2024 16:45 |
| Occurrence, Cytoplasmic vacuolization (hepatocyte) leads to Induction, Microvesicular fat | December 03, 2016 16:38 |
| Occurrence, Cytoplasmic vacuolization (hepatocyte) leads to Formation, Mallory body | December 03, 2016 16:38 |
| Occurrence, Ballooning degeneration (hepatocyte) leads to Induction, Microvesicular fat | December 03, 2016 16:38 |
| Occurrence, Ballooning degeneration (hepatocyte) leads to Formation, Mallory body | December 03, 2016 16:38 |
| Occurrence, Cytoplasmic vacuolization (Bile duct cell) leads to Induction, Microvesicular fat | December 03, 2016 16:38 |
| Occurrence, Cytoplasmic vacuolization (Bile duct cell) leads to Formation, Mallory body | December 03, 2016 16:38 |
| Occurrence, Cytoplasmic vacuolization (kupffer cell) leads to Induction, Microvesicular fat | December 03, 2016 16:38 |
| Occurrence, Cytoplasmic vacuolization (kupffer cell) leads to Formation, Mallory body | December 03, 2016 16:38 |
| Induction, Microvesicular fat leads to Formation, Liver fibrosis | December 03, 2016 16:38 |
| Formation, Mallory body leads to Formation, Liver fibrosis | December 03, 2016 16:38 |
Abstract
A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance.
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Drug-induced phospholipidosis (DIPL) is one of the lipid storage disorders, and some of the cationic amphiphilic drugs (CADs) lead to phospholipids accumulation in the lysosome. Some patients with phospholipidosis have been reported with steatosis, cirrhosis, and fibrosis but the mechanism of their association has not been clarified. CADs can easily pass through membranes due to their amphiphilic character and accumulate in the lysosome of the hepatocyte or alveolar macrophage. These drugs inhibit the activity of lysosomal phospholipase A2 by binding with enzyme or phospholipid, which causes phospholipids to accumulate in lysosome and form a lamellar body. Therefore, CADs led to phospholipidosis along with lysosomal dysfunction. Lysosomes are the predominant digestive organelle and it has the hydrolytic enzymes that degrade peptides, nucleic acids, carbohydrates, and lipids. Lysosomal dysfunction induced to lipid accumulation in the cytosol by inhibiting the lipid metabolism. And lysosomal membrane potential is changed due to accumulating CADs in lysosome and it induced the lysosomal cell death and mitochondrial dysfunction by secondary effects. To develop the AOP for phospholipid and hepatotoxicity, we survey the public literature. At present, direct evidence between phospholipidosis and hepatotoxicity is still lacking, but we try to explain using the AOP framework.
AOP Development Strategy
Context
Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below.
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Strategy
Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used).
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Summary of the AOP
This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed.
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Events:
Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP.
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Key Events (KE)
A measurable event within a specific biological level of organisation.
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Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP.
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| Type | Event ID | Title | Short name |
|---|
| MIE | 828 | Inhibition, Phospholipase A | Inhibition, Phospholipase A |
| KE | 829 | Damage, Lipid bilayer | Damage, Lipid bilayer |
| KE | 831 | Disturbance, Lysosomal function | Disturbance, Lysosomal function |
| KE | 177 | Mitochondrial dysfunction | Mitochondrial dysfunction |
| KE | 833 | Occurrence, Cytoplasmic vacuolization (hepatocyte) | Occurrence, Cytoplasmic vacuolization (hepatocyte) |
| KE | 835 | Occurrence, Ballooning degeneration (hepatocyte) | Occurrence, Ballooning degeneration (hepatocyte) |
| KE | 837 | Occurrence, Cytoplasmic vacuolization (kupffer cell) | Occurrence, Cytoplasmic vacuolization (kupffer cell) |
| KE | 838 | Induction, Microvesicular fat | Induction, Microvesicular fat |
| KE | 839 | Formation, Mallory body | Formation, Mallory body |
| KE | 836 | Occurrence, Cytoplasmic vacuolization (Bile duct cell) | Occurrence, Cytoplasmic vacuolization (Bile duct cell) |
| AO | 840 | Formation, Liver fibrosis | Formation, Liver fibrosis |
Relationships Between Two Key Events (Including MIEs and AOs)
This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page.
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| Title | Adjacency | Evidence | Quantitative Understanding |
|---|
Network View
This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs.
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Prototypical Stressors
A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented.
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Life Stage Applicability
The life stage for which the AOP is known to be applicable.
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| Life stage | Evidence |
|---|---|
| 1 to < 3 months | High |
| Adults | High |
Taxonomic Applicability
Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.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.
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Sex Applicability
The sex for which the AOP is known to be applicable.
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| Sex | Evidence |
|---|---|
| Male | High |
| Unspecific | Low |
Overall Assessment of the AOP
Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment).
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Domain of Applicability
Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context.
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Essentiality of the Key Events
The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs.
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Evidence Assessment
Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP.
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Known Modulating Factors
Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs.
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| Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
|---|---|---|
Quantitative Understanding
Optional field to provide quantitative weight of evidence descriptors.
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Considerations for Potential Applications of the AOP (optional)
Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment.
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References
List of the literature that was cited for this AOP.
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