Friday, May 12, 2017

Free-Radical Chain Reactions that Spread Damage and Destruction

One way radiation damages tissue is by producing free radicals, also known as reactive oxygen species. In Chapter 16 of Intermediate Physics for Medicine and Biology, Russ Hobbie and I discuss these molecules:
High-LET [linear energy transfer] radiation produces so many ion pairs along its path that it exerts a direct action on the cellular DNA. Low-LET radiation can also ionize, but it usually acts indirectly. It ionizes water (primarily) according to the chemical reaction

H2O → H2O+ + e- .

The H2O+ ion decays with a lifetime of about 10-10 s to the hydroxyl free radical:

H2O+ + H2O → H3O+ + OH .

This then produces hydrogen peroxide and other free radicals that cause the damage by disrupting chemical bonds in the DNA.
Free radicals are produced not only by water, but also by oxygen, O2. Tissues without much oxygen (such as the ischemic core of a tumor) are resistant to radiation damage.

Nic Lane’s book Oxygen: The Molecule that Made the World explains how radiation interacts with tissue through free radicals. In his Chapter 6, Treachery in the Air: Oxygen Poisoning and X-Irradiation: A Common Mechanism, he writes:
"A free radical is loosely defined as any molecule capable of independent existence that has an unpaired electron. This tends to be an unstable electronic configuration. An unstable molecule in search of stability is quick to react with other molecules. Many free radicals are, accordingly, very reactive…

The three intermediates formed by irradiating water, the hydroxyl radicals, hydrogen peroxide and superoxide radicals, react in very different ways. However, because all three are linked and can be formed from each other, they might be considered equally dangerous…

Hydroxyl radicals (OH) are the first to be formed. These are extremely reactive fragments, the molecular equivalents of random muggers. They can react with all biological molecules at speeds approaching their rate of diffusion. This means that they react with the first molecules in their path and it is virtually impossible to stop them from doing so. They cause damage even before leaving the barrel of the gun…

If radiation strips a second electron from water, the next fleeting intermediate is hydrogen peroxide (H2O2)…Hydrogen peroxide is unusual in that it lies chemically exactly half way between oxygen and water. This gives the molecule something of a split personality. Like a would-be reformed mugger, whose instinct is pitted against his judgement, it can go either way in its reactions….[A] dangerous and significant reaction, however, takes place in the presence of iron, which can pass electrons one at a time to hydrogen peroxide to generate free radicals. If dissolved iron is present, hydrogen peroxide is a real hazard…

The third of our intermediates … [is] the superoxide radical (O2-). Like hydrogen peroxide, the superoxide radical is not terribly reactive. However, it too has an affinity for iron…
In summary, then, the three intermediates between water and oxygen operate as an insidious catalytic system that damages biological molecules in the presence of iron. Superoxide radicals release iron from storage depots and convert it into the soluble form. Hydrogen peroxide reacts with soluble iron to generate hydroxyl radicals. Hydroxyl radicals attack all proteins, lipids and DNA indiscriminately, initiating destructive free-redical chain reactions that spread damage and destruction."
I fear that physics and biology alone are not enough to understand how radiation interacts with tissue; we need some chemistry too.

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