SN2 SHORT NOTE 5M ★ High-yield

Describe the generation of free radicals and the mechanisms of free radical injury.

Pathology · 2nd Professional — Para-Clinical

Definition

Free radicals are chemical species with a single unpaired electron in an outer orbital, which makes them extremely unstable and reactive.

They react with adjacent molecules and convert those into radicals in turn, so damage propagates as an autocatalytic chain reaction

Important Reactive Oxygen Species

Species	Formula	Origin
Superoxide anion	O2−	Incomplete reduction of oxygen in the mitochondrial chain; NADPH oxidase
Hydrogen peroxide	H2O2	From superoxide by superoxide dismutase
Hydroxyl radical	OH•	The most reactive and most damaging; from the FENTON reaction with Fe2+, the Haber–Weiss reaction, and radiolysis of water
Nitric oxide	NO	Nitric oxide synthase; combines with superoxide to give peroxynitrite
Hypochlorite	HOCl	Myeloperoxidase in the neutrophil

Generation

Normal metabolism — about 1–3% of the oxygen used in respiration leaks as superoxide
Inflammation — the respiratory burst in phagocytes generates radicals deliberately, to kill organisms
Ionising radiation — splits water into hydroxyl radicals
Transition metals — iron and copper catalyse radical formation
Drug metabolism — carbon tetrachloride to CCl3• and paracetamol to NAPQI by cytochrome P450
Reperfusion after ischaemia; cigarette smoke; ultraviolet light

Mechanisms of Damage

Target	Damage	Consequence
Lipids	Lipid peroxidation of polyunsaturated fatty acids in membranes	Loss of integrity of plasma, mitochondrial and lysosomal membranes
Proteins	Oxidation of side chains and cross-linking, especially of sulphydryl groups	Loss of enzyme activity; misfolding and degradation
DNA	Single-strand breaks and base modification	Mutation, ageing and malignant transformation

Antioxidant Defences

Category	Agents
Enzymatic	Superoxide dismutase; catalase in peroxisomes; glutathione peroxidase, which requires selenium
Non-enzymatic	Vitamin E in membranes; vitamin C in the aqueous phase; beta-carotene; glutathione
Metal-binding proteins	Transferrin, ferritin, ceruloplasmin — sequester iron and copper so they cannot catalyse radical formation

CLINICAL PEARL

The body keeps iron bound for a reason. Free iron drives the Fenton reaction and generates hydroxyl radicals, so nearly all body iron is held in transferrin or ferritin. That is why iron overload in haemochromatosis and repeated transfusion damages the liver, heart and pancreas — the mechanism is oxidative.

Applied Aspects

Reperfusion injury — restoring flow to ischaemic myocardium or bowel initially worsens the damage; relevant to thrombolysis, angioplasty and transplantation
Paracetamol poisoning — NAPQI depletes glutathione; N-acetylcysteine restores it and is effective if given early
Chronic granulomatous disease shows the other side — radicals are necessary; without NADPH oxidase the neutrophil cannot kill
Retinopathy of prematurity and bronchopulmonary dysplasia follow oxygen therapy in a newborn whose antioxidant defences are immature
Antioxidant vitamin supplements have not reduced cardiovascular disease or cancer in large trials, and beta-carotene increased lung cancer in smokers — a caution against reasoning from mechanism straight to therapy

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