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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 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 the 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 hydroxyl radical (OH.).

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 O2- 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 an enzyme the produces

nitric oxide, which helps in 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 intohydroxyl 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, like an endless

loop. So, over time, free radicals formed as a result of the Fenton reaction slowly

damage cells in various organs, that can cause cell death and then lead to tissue fibrosis.

Free radicals are also produced following ischemia, or reduced blood flow to an organ

or tissue. At a cellular level, ischemic injury can lead to the production of ROS by the mitochondria.

If blood flow returns to the ischemic tissue, it's called reperfusion, and it brings more

oxygen. Unfortunately, though, all this oxygen reacts with the pre-existing free radicals

to form more, causing more cell damage. This is called reperfusion injury. Finally, free

radicals can also be generated when chemicals or medication that enter the body are being

metabolised by the liver. For example, when the liver breaks down a drug like acetaminophen,

or Tylenol, a lot of free radicals are generated and this could cause massive damage to the

liver.

Since the body generates free radicals even under normal conditions, there are certain

defense mechanisms in place to keep them in check. One of them is antioxidants like vitamin

A, vitamin C, and vitamin E, which donate electrons to neutralize free radicals, and

protect the cells. Another molecule in our body called glutathione acts as an antioxidant

and neutralizes H2O2. In order to function, 2 glutathiones need to be in the reduced state

where they can donate an electron and a proton to the H2O2 and convert it into harmless water.

However, this oxidizes glutathione, so before it can get back to work, an enzyme called

glutathione reductase uses NADPH as an electron donor and reduces the oxidized glutathione

back into its working state. After giving up its electron, the NADPH becomes NADP+.

So to replenish the supply of NADPH, an enzyme called glucose-6-phosphate dehydrogenase enzyme,

or G6PD, reduces NADP+ back to NADPH by oxidizing glucose-6-phosphate. Glucose-6-phosphate is

a metabolite of glucose so we usually have a ready supply of this molecule as long as

we are not starving.

Another defence mechanism is metal carrier proteins which bind to the metal ions and

help in transporting or storing them. This way, it’s sort of like the ions are hidden

away, and so are not able to generate free radicals. For example, transferrin which binds

to iron, and ceruloplasmin which binds to copper and carry them in the blood. And finally,

there are also free radical scavenging enzymes which convert the free radicals into harmless

substances like water. Superoxide dismutase, takes superoxide and converts it into hydrogen

peroxide. Catalase converts hydrogen peroxide into water in peroxisomes, and glutathione

peroxidase does the same in the cytoplasm.

When the amount of free radicals produced overwhelms the defence mechanisms, cell damage

starts to occur. Free radicals can react with the lipids in the cell membrane, causing lipid

peroxidation. For example, let’s say a hydroxyl radical has attacked this particular lipid

molecule. This molecule is now left with an unpaired electron, so it in turn grabs an

electron from the next lipid molecule, setting up a sort of chain reaction which ends up

damaging the cell membrane. Free radicals can also cause oxidative modification of proteins,

which affects the function of enzymes and other structural proteins. Oxidation of DNA

can cause breaks in the DNA strands, and can also introduce mutations which increase the

risk of cancer.

All right, as a quick recap… Free radicals are chemical species with an unpaired electron,

which can damage the cells by oxidizing the lipid, proteins, and even the DNA. They are

produced in the body physiologically by the electron transport chain, and pathologically

during inflammation, exposure to ionizing radiation, metabolism of chemicals or medication

like acetaminophen, build up of metals like iron or copper, and reperfusion of ischemic

tissue. Free radicals are normally kept in check by antioxidants, metal carrier proteins

and free radical scavenging enzymes.