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AOP: 130
Title
Phospholipase A2 (LPLA2) inhibitors leading to hepatotoxicity
Short name
Graphical Representation
Point of Contact
Contributors
- Jung-Hwa Oh
- Seokjoo Yoon
- Agnes Aggy
Coaches
- Cinzia La Rocca
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
---|---|---|---|---|
1.39 | Under Development |
This AOP was last modified on May 26, 2024 20:39
Revision dates for related pages
Page | Revision Date/Time |
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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
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
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
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)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
1 to < 3 months | High |
Adults | High |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Male | High |
Unspecific | Low |
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Evidence Assessment
Known Modulating Factors
Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
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