Unit 2 Mechanisms Flashcards
Renal Tox: Cadmium
Cd binds to MT in the liver -> Cd blocks receptors in the kidney -> Cd increases -> **inhibits ETC ** -> mitochondrial dysfunction -> ROS -> apoptosis
Renal Tox: Silica
Silica inhalation -> Silica accumulates in the Proximal Convulated Tubule -> Mitochondrial dysfunction
-> ROS -> inflammation -> fibrosis -> chronic kidney damage -> decreased eGFR
Renal Tox: NSAIDS
- Glomerular toxicant
- **Cox-2 **inhibits PGE2 -> vasoconstriction -> decreased eGFR
Liver Tox: Acetaminophen (APAP)
- APAP metabolized into NAPQI -> decreased GSH -> protein adducts -> ROS -> necrosis -> DAMPS -> innate immune response -> inflammation -> tissue repair
Liver Tox: TCE
TCE is metabolized into TCE epoxide -> acyl chloride -> reactive aldehyde -> irreversibly binds to DNA and proteins -> genotoxicity
Liver Tox: CCL4
Necrosis -> Fibrous -> Cirrohosis
Liver Tox: Ethanol
Ethanol -> ADH -> Aldehyde -> Acetic Acid -> Excreted
Liver Tox: Ethanol Overdose
Ethanol metabolized by CYP450 -> ROS -> mitochondrial dysfunction -> apoptosis
Liver Tox: APAP and Ethanol
- Ethanol is metabolized by CYP450
- APAP metabolized into NAPQI -> protein adducts -> ROS -> mitochondrial dysfunction -> necrosis
NAC -> Increases depleted GSH
Respiratory Tox: Silica
Silica inhalation -> immune response -> proteolytic enzyme release -> cytokine release -> chronic inflammation -> fibroblast proliferation -> fibrosis
Respiratory Tox: Coal Dust
Coal dust inhaltion -> immune response -> chronic exposure -> alveolar wall injury -> emphysema (alveoli lung damage, shortness of breath)
Respiratory Tox: Asbestos
Asbestos inhalation -> immune response -> chronic inflammation -> mitochondrial dysfunction -> ROS -> dna damage -> high cell turn over rate -> mutations -> cancer
Respiratory Tox: PM 2.5
- Small, toxic particulate matter that damages the alveolar region of the lungs
Respiratory Tox: ARDS - DAD
- Exudative (alveolar-capillary barrier damage -> edema)
- Proliferative (edema reabsorbed -> recovery of alveolar-capillary barrier)
- Fibrotic (recovery not possible, decreased lung compliance)
Respiratory Tox: ARDS - DAD Mechanism
Hyperoxia damages ATI pneumocytes and alveolar macrophages -> ROS -> macrophages release neutrophil chemotactic compounds -> neutrophil recruitment -> lung tissue damage
Respiratory Tox: High Pb
High Pb -> more blood soluble -> slower onset and offset time
Respiratory Tox: Lower Pb
Lower Pb -> less blood soluble -> faster onset and offset
Cardio Tox: Blood Flow
RA -> Tricuspid Valve -> RV -> Pulmonary Valve -> Lungs -> LA -> Mitral Valve -> LV -> Aorta -> Body
**Exception: Deoxygenated blood from the heart to the veins via the Pulmonary Artery **
Cardio Tox: Doxorubicin
- Inflammatory response -> macrophages
Cardio Tox: TCA
TCA -> HERG channel inhibitor -> QT prolongation -> heart arrythmia
Cardio Tox: Glycosides
Glycosides -> Na/K ATPase inhibitor -> increase in Ca 2+
-> mitochondrial dysfunction -> ROS -> protein adducts
Cardio Tox: Action Potentials
Na⁺ influx (Phase 0) → K⁺ efflux + Cl⁻ (Phase 1) → Ca²⁺ influx / K⁺ efflux (Phase 2) → K⁺ efflux (Phase 3) → Stable K⁺ balance (Phase 4).
Dermal Tox: Irritant Dermatitis
- Low doses, multiple encounters
- RXNS at skin point of contact
- No immune response
- Chemical burn (Ammonia)
Dermal Tox: Allergic Irritant
- Previous encounter needed
- Type IV Hypersensitivy (Langerhan Cells -> T cells -> Th1)
- Delayed RXN (48 hrs - 72 hrs)
- Poison Ivy
Dermal Tox: Major Skin Components
- Epidermis (kertainocytes, langerhand cells, merkel cells, melanocytes)
- Dermis (blood vessels, collagen, glands)
- Hypodermis (adipose tissue)
Dermal Tox: Absorption
- Straneum Corenum -> Epidermis -> Dermis
- Hydrophobic, Lipophilic
- Molecular weight, concentration, duration
Dermal Tox: UV Radiation DNA Damage
- UV Radiation -> Thymine dimers -> DNA damage -> mutations -> Cox 1/2 activated -> PGE2 -> PGE2 binds EPI and EP4 receptors -> inflammation -> cell proliferation -> cancer
Dermal Tox: Protoporphyria
Genetic defect inhibits heme production -> protoporphyria build up -> UV radiation interacts w/ protoporphyria and oxygen -> ROS -> protein adducts -> lipid peroxidase -> tissue damage
Neuro Tox: Methyl Mercury
Sulfhydrl bindings -> ROS -> mitochondrial dysfunction -> inhibits glycolysis, protein and nucleic acid synthesis
Neuro Tox: Domoic Acid
Increase in glutamate -> increase in Ca2+ -> mitochondrial dysfunction -> loss of ATP -> neuronal death
Neuro Tox: Carbon disulfide/n-hexane
- crosslinking neurofilament proteins -> adducts -> protein modification -> distal axonopathy
Neuro Tox: Triethylin
Metabolic inhibitor -> mitochondrial dysfunction -> loss of ATP in the oligodendrocytes
Neuro Tox: Colchicine/Taxol
destabilizies microtubles/stabilizes microtubules
Neuro Tox: Organophosphates
Organophosphates bind to Serine residue -> inhibits AchE from converting into Ach -> overstimulated nervous system
Neuro Tox: Botox
Botox inhibits the release of Ach at the synapse by targeting and cleaving SNARE proteins -> muscle paralysis
Neuro Tox: Cocaine and Amphetamine
blocks dopamine reuptake -> dopamine accumulates in the synpases -> ROS -> mitochondrial dysfunction -> neurodegeneration
Immuno Tox: Innate
- Fast, non specific
- No memory
- Macrophages, Neutrophils
- Phagocytosis
Immuno Tox: Adapative
- Slow, specific
- Memory
- T cells -> B cells
Immuno Tox: Hypersensitivity IV
- Fast
- Langerhan cells -> T cells -> Th1
Immuno Tox: Hypersensitivy I