STEPTRACKERGENERAL PRINCIPLES | PATHOLOGY + BIOCHEMISTRY | HIGH-YIELD REVIEW

Free Radical Injury

Molecules with an unpaired electron that attack membranes, proteins and DNA — and the systems that disarm them.

FOCUS ON
Learn the sources: radiation, metals (Fenton reaction), inflammation, drug metabolism, reperfusion. Then the scavengers: SOD, catalase, glutathione peroxidase, antioxidant vitamins. Acetaminophen, CCl₄ and reperfusion are the favorite vignettes. The hydroxyl radical (•OH) does the most damage.
SOURCE
HOW RADICALS FORM
WHAT IT DAMAGES
CLASSIC SETTING
Normal metabolism
oxidative phosphorylation
Partial reduction of O₂ yields superoxide (O₂•⁻), H₂O₂ and •OH as by-products.
Low-level baseline damage, normally fully scavenged
Contributes to aging (lipofuscin)
Ionizing radiation
water hydrolysis
Radiation splits water into •OH.
DNA strand breaks → apoptosis, mutation, fibrosis
Radiation pneumonitis, later cancer risk
Transition metals
Fenton reaction
Free Fe²⁺ or Cu⁺ + H₂O₂ → •OH.
Lipid peroxidation of membranes in liver, pancreas, heart, brain
Hemochromatosis (iron), Wilson disease (copper)
Inflammation
respiratory burst
NADPH oxidase makes O₂•⁻; MPO converts H₂O₂ + Cl⁻ into HOCl (bleach).
Microbes — and surrounding host tissue
Absent burst = chronic granulomatous disease
Drugs & toxins
cytochrome P450
CCl₄ → CCl₃• radical. Acetaminophen → NAPQI, which uses up glutathione.
Centrilobular (zone 3) hepatocyte necrosis; fatty change from ↓ apolipoprotein synthesis
Acetaminophen overdose → give N-acetylcysteine
Reperfusion
return of O₂
Restored blood brings O₂, neutrophils and xanthine oxidase activity → burst of ROS plus Ca²⁺ influx.
Further injury to cells that survived ischemia; contraction bands in myocardium
Troponin keeps rising after a successful stent or thrombolysis
Supplemental O₂
hyperoxia
High inspired O₂ produces excess ROS in developing tissue.
Retinal vessels, immature lung
Retinopathy of prematurity, bronchopulmonary dysplasia

Mechanism — the radical chain and its brakes

O₂Partly reduced
→
O₂•⁻Superoxide
→
H₂O₂via SOD
→
•OHvia Fe²⁺ (Fenton)
→
DamageLipid peroxidation · protein oxidation · DNA breaks

Brakes: catalase and glutathione peroxidase turn H₂O₂ into water before it reaches iron. Glutathione is kept reduced by NADPH from the HMP shunt (G6PD).

Scavenger systems

DEFENSE
REACTION
CLINICAL LINK
Superoxide dismutase
O₂•⁻ → H₂O₂
SOD1 mutation → familial ALS
Catalase
H₂O₂ → H₂O + O₂
Catalase⁺ organisms threaten CGD patients
Glutathione peroxidase
2 GSH + H₂O₂ → GSSG + 2 H₂O
G6PD deficiency: ↓ NADPH → ↓ GSH → hemolysis
Antioxidant vitamins
A, C, E neutralize radicals
Vitamin E deficiency → hemolysis, neuropathy
Metal carriers
Transferrin, ferritin, ceruloplasmin bind free metals
Keep Fe/Cu out of the Fenton reaction

How it's tested

COMMON CONFUSIONAcetaminophen and CCl₄ both injure zone 3 (centrilobular) — that zone has the most P450 and the least O₂.
THE TRAPA patient stented for an MI has troponin that rises further and shows contraction band necrosis. This is reperfusion injury, not a failed procedure.
YOUR APPROACHName the source of radicals, then the brake that failed: no respiratory burst → CGD; no NADPH → G6PD deficiency; no SOD1 → ALS; free iron → hemochromatosis.

If you see… think…

Troponin rising after successful reperfusion → reperfusion (ROS) injury
Acetaminophen overdose, ALT in thousands → NAPQI, glutathione depletion → N-acetylcysteine
Solvent exposure, fatty liver, zone 3 necrosis → CCl₄ → CCl₃•
Bronze skin, diabetes, cirrhosis → iron-driven Fenton reaction
Premature infant on high O₂, retinal neovascularization → retinopathy of prematurity
Familial motor neuron disease → SOD1 mutation
Hemolysis with Heinz bodies after fava beans → G6PD deficiency (↓ NADPH)
Recurrent S aureus and Aspergillus infections → CGD (no NADPH oxidase)
Lung fibrosis months after chest radiation → •OH from water hydrolysis