Free Radicals and Antioxidants
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Direct answer
The hydroxyl radical annihilates whatever molecule it meets within nanoseconds of its birth — generated chiefly by the Fenton reaction (Fe2+ + H2O2 → Fe3+ + OH− + OH•) — and it is the reason antioxidant defence is layered. Superoxide (O2•−) leaks from mitochondrial electron transport and bursts from phagocyte NADPH oxidase; superoxide dismutase converts two superoxides to hydrogen peroxide, which catalase (peroxisomes) and glutathione peroxidase (selenium-dependent) then reduce to water. Non-enzymatic scavengers — ascorbate in aqueous compartments, α-tocopherol in membranes, β-carotene, uric acid and albumin — absorb the rest. Clinically, radical injury underlies oxygen toxicity, retinopathy of prematurity, reperfusion injury after thrombolysis, iron overload (haemochromatosis) and paracetamol poisoning, where the NAPQI metabolite exhausts glutathione.
What you must remember
- Enzymatic trio: superoxide dismutase (cytosolic Cu/Zn SOD1, mitochondrial Mn SOD2) → H2O2; catalase (peroxisomal, very high turnover) → water and oxygen; glutathione peroxidase (a selenoenzyme reducing H2O2 and lipid peroxides at glutathione's expense, producing GSSG, which glutathione reductase regenerates using NADPH).
- Sources: mitochondrial electron leakage (complex I and III), phagocyte respiratory burst (NADPH oxidase and myeloperoxidase), ionising radiation, drugs (paracetamol, doxorubicin, alcohol via CYP2E1), and ischaemia-reperfusion.
- Chronic granulomatous disease: NADPH oxidase deficiency — no respiratory burst, recurrent catalase-positive staphylococcal and fungal abscesses, negative nitroblue tetrazolium test; contrast myeloperoxidase deficiency (candidal infections, mild).
- Retinopathy of prematurity: supplemental oxygen in preterm neonates retards retinal vascular growth; subsequent relative hypoxia drives vascular endothelial growth factor-mediated proliferation — screening protocols target infants under about 1,500 g or before 32 weeks, per national programme guidance.
- Reperfusion injury: restored oxygen floods ischaemic tissue with substrate for radical generation (xanthine oxidase pathway) — the paradox that opening the artery injures the tissue it saves.
- Iron and copper overload: Fe2+ and Cu+ catalyse Fenton chemistry — haemochromatosis liver fibrosis and Wilson disease oxidant injury both stem partly from this.
- Selenium deficiency: Keshan disease, an endemic dilated cardiomyopathy from low-soil selenium regions of China — the classical justification for glutathione peroxidase's trace element.
- Nutritional antioxidants: vitamin C regenerates vitamin E; selenium is best known through the enzyme, not the tablet.
A worked case: paracetamol and the glutathione ledger
A young woman takes 30 tablets of paracetamol over a suicidal evening and presents 20 hours later with vomiting and right upper quadrant tenderness; alanine aminotransferase is 3,500 U/L. Walk the chemistry: at therapeutic doses about 90% of paracetamol is glucuronidated or sulphated and 5% or less goes through CYP2E1 to NAPQI, mopped up by glutathione; in overdose the conjugation paths saturate, NAPQI floods, and glutathione stores collapse — the surviving NAPQI then covalently binds hepatic protein thiols, producing centrilobular necrosis. N-acetylcysteine is glutathione's replacement part: it replenishes cysteine, resynthesises glutathione, and directly conjugates NAPQI; given within 8 hours it is near-completely protective, and even at 20 hours it improves outcomes. The Rumack-Matthew nomogram, plotted from ingestion time and level, guides risk where levels are available — otherwise a staggered or unknown-time overdose is treated on index of suspicion.
Where students slip
"Most reactive radical" answers vary; the hydroxyl radical holds the title, and the Fenton reaction producing it is the expected supporting mechanism. Second, superoxide dismutase is said to "detoxify" — it converts one radical into another (hydrogen peroxide), which is itself handled by catalase and glutathione peroxidase; the defence is a relay, not a single enzyme. Third, glutathione peroxidase's selenium is forgotten, letting Keshan disease and selenium supplementation questions fall. Fourth, chronic granulomatous disease and G6PD deficiency are again separable neighbours here: one cannot make the oxidant weapon, the other cannot defend against it. Fifth, retinopathy of prematurity is framed as "oxygen burns the retina"; the two-phase mechanism (vaso-obliteration then hypoxia-driven proliferation) is what a paediatrics viva wants, and it explains why careful oxygen titration, not oxygen denial, is the answer.
Frequently asked questions
Which free radical is the most reactive, and how is it generated?
The hydroxyl radical, produced by the Fenton reaction between hydrogen peroxide and ferrous iron (and amplified by the superoxide-driven Haber-Weiss cycle).
What are the three principal antioxidant enzymes and their cofactors?
Superoxide dismutase (Cu/Zn or Mn), catalase (haem) and glutathione peroxidase (selenium), operating as a sequential relay ending in water.
Why does paracetamol overdose cause hepatic necrosis?
Saturated conjugation diverts the drug to CYP2E1-derived NAPQI, which depletes glutathione and binds hepatocyte protein thiols — treated by N-acetylcysteine.
What is the mechanism of chronic granulomatous disease?
Absent NADPH oxidase denies phagocytes their oxidative burst, so catalase-positive organisms survive inside cells, and granulomas form.
Why does restoring blood flow worsen ischaemic injury?
Reperfusion delivers oxygen and neutrophils to tissue loaded with hypoxanthine, regenerating radicals through xanthine oxidase — the oxygen paradox in clinical form.