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Free radicals and cellular injury

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Free radicals and cellular injury

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Free radicals and cellular injury

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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? 

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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.

Now free radicals are molecules with only one electron, or an unpaired electron, in their outer orbital.

Free radicals have a habit of stealing electrons from any molecule they come across to make themselves stable and it’s what causes all the trouble and potentially can cause cellular injury.

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 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 process of making ATP by donating electrons to complexes embedded within the inner mitochondrial membrane.

Together, they form the electron transport chain, which pass electrons from complex to complex, and finally to oxygen, creating a proton gradient that will be used to make ATP.

The final step of this process involves a molecule called cytochrome c oxidase, sometimes known as complex IV, which transfers electrons to oxygen.

Normally, when oxygen gets four electrons, it gets converted into water.

But when oxygen doesn’t get all four electrons, then it will have unpaired electrons in its orbital, 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 (O2−) If it gets two electrons, it becomes hydrogen peroxide, or H2O2, and then 3 electrons, it’s the hydroxyl radical (OH.).

There are also pathological conditions where free radicals can be generated.

First, they can be produced during 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.

Another enzyme, superoxide dismutase, can take these ions and combine them with hydrogen ions to form hydrogen peroxide.

This process of producing superoxide ions and hydrogen peroxide is called the respiratory burst.

Phagocytes also have a type of nitric oxide synthase, which is an enzyme that produces nitric oxide, which helps to kill the pathogen.

But what nitric oxide also does is that, it reacts with superoxide ions to form peroxynitrite free radical (ONOO—). 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 from water, converting it into 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 are 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 be reduced back to iron 2+ via hydrogen peroxide again, creating a peroxide radical and a proton, and then the cycle repeats, like an endless loop.

So, over time, free radicals formed as a result of the Fenton reaction slowly damage cells in various organs, and that can cause cell death and then lead to tissue fibrosis.