Free Radical Injury Flashcards
Free Radical
Chemical Species w/ unprotected e- in outer orbit
How are Free Radicals Generated Physiologically?
Oxidative Phosphorylation
Cytochrome C Oxidase donates e- down ETC to O2, generating a proton gradient that drives formation of ATP
O2 ↓e- Superoxidase Radical ↓e- H2O2 ↓e- Hydroxyl Radical ↓e- H2O
If O2 receives 1 - 3 e-, free radical formation is physiologic
How are Free Radicals Generated Pathologically?
Ionizing Radiation
Inflammation
Metals
Drugs & Chemicals
Free Radical Formation via Ionizing Radiation
Hydroxyl Radical (Most damaging of all free radicals)
Free Radical Formation via Inflammation
PMNs kill via O2 dependent or independent mechanisms
O2 Dependent:
Oxidative Burst
NADPH Oxidase turns O2 → Superoxide
Superoxide Dysmutase turns Superoxide → H2O2
Myeloperoxidase turns H2O2 → HOCl (Bleach)
Free Radical Formation via Metals
Iron - Fenton Reaction (Fe generates free radicals, most commonly Hydroxyl Radical)
Ex: Hemochromatosis
- Cirrhosis & other tissue damage from free radicals
Copper - Wilson’s Disease
Tissue damage from excess free radicals
Free Radical Formation via Drugs & Chemicals
Drugs: Acetaminophen → P450 Metabolism → Free radicals generated
Chemicals: CCl4
Mechanism of Free Radical Damage
Peroxidize lipids (this affects membranes!) Oxidizes DNA (oncogenesis) & proteins
Elimination of Free Radicals
Antioxidants - Vitamin A, C, E
Enzymes - SOD, Glutathione Peroxidase, Catalase
Metal Carrier Proteins (Transferrin, Ferritin)
Enzyme to eliminate Superoxide Radical
Superoxide Dysmutase (SOD)
Enzyme to eliminate H2O2
Catalase
Enzyme to eliminate Hydroxyl Radical
Glutathione Peroxidase
Most damaging free radical
Hydroxyl Radical
CCl4 Free Radical Injury
CCl4 is a Dry Cleaning Agent
Converted to CCL3 by P450 → Hepatocyte damage
Initially reversible:
Cellular swelling → RER swelling → Protein Synthesis ↓ → Lack of Apolipoprotein → Fat can’t exit liver → Fatty changes
Apolipoprotein
In liver
Helps fat exit the cells in repackaged forms
