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. More help

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. More help
Inhibition of LPLA2, hepatotoxicity

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. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help
  • Jung-Hwa Oh, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea
  • Seokjoo Yoon, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea
  • Hyun Jegal, Department of Human and Environmental Toxicology, University of Science & Technology, Daejeon, 34113, Republic of Korea

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.   More help
Agnes Aggy   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Jung-Hwa Oh
  • Seokjoo Yoon
  • Agnes Aggy

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under Development: Contributions and Comments Welcome Under Development 1.39 Included in OECD Work Plan
This AOP was last modified on July 16, 2022 18:37

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
Injury, Mitochondria 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
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 Injury, Mitochondria December 03, 2016 16:38
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
Injury, Mitochondria leads to Occurrence, Cytoplasmic vacuolization (hepatocyte) December 03, 2016 16:38
Injury, Mitochondria leads to Occurrence, Ballooning degeneration (hepatocyte) December 03, 2016 16:38
Injury, Mitochondria leads to Occurrence, Cytoplasmic vacuolization (Bile duct cell) December 03, 2016 16:38
Injury, Mitochondria leads to Occurrence, Cytoplasmic vacuolization (kupffer cell) December 03, 2016 16:38
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. More help

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. More help

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). More help

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. More help

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. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
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 832 Injury, Mitochondria Injury, Mitochondria
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. More help
Title Adjacency Evidence Quantitative Understanding
Inhibition, Phospholipase A leads to Damage, Lipid bilayer adjacent High
Inhibition, Phospholipase A leads to Disturbance, Lysosomal function adjacent High
Inhibition, Phospholipase A leads to Injury, Mitochondria adjacent High
Damage, Lipid bilayer leads to Occurrence, Cytoplasmic vacuolization (hepatocyte) adjacent Low
Damage, Lipid bilayer leads to Occurrence, Ballooning degeneration (hepatocyte) adjacent Low
Damage, Lipid bilayer leads to Occurrence, Cytoplasmic vacuolization (Bile duct cell) adjacent Low
Damage, Lipid bilayer leads to Occurrence, Cytoplasmic vacuolization (kupffer cell) adjacent Low
Disturbance, Lysosomal function leads to Occurrence, Cytoplasmic vacuolization (hepatocyte) adjacent Low
Disturbance, Lysosomal function leads to Occurrence, Ballooning degeneration (hepatocyte) adjacent Low
Disturbance, Lysosomal function leads to Occurrence, Cytoplasmic vacuolization (Bile duct cell) adjacent Low
Disturbance, Lysosomal function leads to Occurrence, Cytoplasmic vacuolization (kupffer cell) adjacent Low
Injury, Mitochondria leads to Occurrence, Cytoplasmic vacuolization (hepatocyte) adjacent Low
Injury, Mitochondria leads to Occurrence, Ballooning degeneration (hepatocyte) adjacent Low
Injury, Mitochondria leads to Occurrence, Cytoplasmic vacuolization (Bile duct cell) adjacent Low
Injury, Mitochondria leads to Occurrence, Cytoplasmic vacuolization (kupffer cell) adjacent Low
Occurrence, Cytoplasmic vacuolization (hepatocyte) leads to Induction, Microvesicular fat adjacent Low
Occurrence, Cytoplasmic vacuolization (hepatocyte) leads to Formation, Mallory body adjacent Low
Occurrence, Ballooning degeneration (hepatocyte) leads to Induction, Microvesicular fat adjacent Low
Occurrence, Ballooning degeneration (hepatocyte) leads to Formation, Mallory body adjacent Low
Occurrence, Cytoplasmic vacuolization (Bile duct cell) leads to Induction, Microvesicular fat adjacent Low
Occurrence, Cytoplasmic vacuolization (Bile duct cell) leads to Formation, Mallory body adjacent Low
Occurrence, Cytoplasmic vacuolization (kupffer cell) leads to Induction, Microvesicular fat adjacent Low
Occurrence, Cytoplasmic vacuolization (kupffer cell) leads to Formation, Mallory body adjacent Low
Induction, Microvesicular fat leads to Formation, Liver fibrosis adjacent High
Formation, Mallory body leads to Formation, Liver fibrosis adjacent High

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. More help

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. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
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. More help
Term Scientific Term Evidence Link
Sprague-Dawley Sprague-Dawley High NCBI
Homo sapiens Homo sapiens High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
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). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

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. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

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. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

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. More help

References

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