AssessmentsFree radicals and cellular injury
Free radicals and cellular injury
USMLE® Step 1 style questions USMLE
An investigator is studying the mechanism of hepatocyte damage in patients with hereditary hemochromatosis. Which of the following is an important cellular defense mechanism used by hepatocytes in hemochromatosis?
Content Reviewers:Rishi Desai, MD, MPH
Contributors:Tanner Marshall, MS
Electrons in an atom are present in spaces called orbitals, and each orbital can fit different pairs of electrons.
Free radicals are molecules with an unpaired electron in their outer orbital.
Now, electrons don’t like to be lonely so free radicals have a habit of stealing electrons from any molecule they come across to make themselves stable.
This causes the victim molecules to be less stable which is why free radicals are a problem.
Now, a free radical is formed when any molecule gains or loses an electron.
In the body, free radicals can be generated physiologically, which means as a part of the normal metabolic processes; or pathologically, which is due to some disease.
A major physiological source of free radicals is cellular respiration, which is also called oxidative phosphorylation.
Oxidative phosphorylation is the body’s process of making ATP through the electron transport chain.
This chain is made up of electron carriers, called complexes, embedded within the inner mitochondrial membrane which pass electrons along like the baton in a relay race.
Together, they form the electron transport chain, which pass electrons from complex to complex.
The final step of this process involves a molecule called cytochrome c oxidase, sometimes known as complex IV, which transfers electrons to molecular oxygen, or simply O2, which then splits into two oxygen atoms.
The transferred electrons make the oxygen atoms electronegative enough to grab two protons, or H+ ions, each from the mitochondrial matrix - making two molecules of H20.
Normally, four electrons are required to convert O2 into two molecules of water.
But when less than four electrons are transferred to oxygen, then it will have unpaired electrons in its orbitals, giving rise to free radicals.
Since these are formed from oxygen, they’re collectively called reactive oxygen species, or simply ROS.
Okay so if oxygen is given one electron, it becomes superoxide (so O2 with a little dot for its extra electron).
If it gets two electrons, it becomes hydrogen peroxide, or H2O2, and then 3 electrons, it’s hydroxyl radical.
There are also pathological conditions where free radicals can be generated.
First, they can be produced during an inflammation by phagocytes like macrophages and neutrophils.
When a pathogen invades the body, the phagocyte gobbles up the pathogen forming a phagolysosome.
These phagocytes also have an enzyme called NADPH oxidase, which gets activated by the lysosomal enzymes, causing NADPH to undergo oxidation, and lose two of its electrons.
Nearby oxygen molecules can grab these electrons to form superoxide ions, or O2- ions.
Another enzyme, superoxide dismutase, can take these ions and combine them with hydrogen ions to form hydrogen peroxide, or H2O2.
This process of producing superoxide ions and hydrogen peroxide is called the respiratory burst.
These ions and molecules destroy pathogens by breaking down their cell membranes and damaging their proteins.
Another way free radicals can be generated is through exposure to ionising radiations like ultraviolet light or X-rays.
When the radiation hits the water in the tissues, it knocks off an electron.
So, if we go back to the previous sequence, and go backwards here from water, you’ll end up at the hydroxyl radical.
Free radicals can also be generated when there’s a build up of metals like copper or iron in the body.
For example, hemochromatosis is a condition where unusually high amounts of iron is absorbed.
All this extra iron, undergoes the Fenton reaction, where molecules of iron 2+ are oxidized by hydrogen peroxide, producing iron 3+ and the hydroxyl radical and hydroxide ion as byproducts; now, iron 3+ can than be reduced back to iron 2+ via hydrogen peroxide again, creating a peroxide radical and a proton, and then the cycle repeats, creating this like endless loop of free radical generation.
So, over time, all these deposits of iron slowly damage the cells in the various organs by free radical generation, that case cell death and then lead to tissue fibrosis.