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Anthracycline Side Effects - Mode of Action

Posted Oct 01 2008 8:09pm
How the anthracyclines cause heart damage – the biochemistry of it all. This post will probably take a few days as I try to get my head around it and then explain it in as simple terms as I can muster.

First off, there is no one mechanism, but it all involves “free radicals” that are widely bandied about in the media, conventional and the full range of complementary medicine as harmful. But what exactly is a free radical? Why is it harmful ? And why to the heart ? And why should anthracyclines contribute to this?

Free radicals

The two major free radicals are known as “superoxide” and “hydroxyl”. I´ll illustrate with the superoxide.

A normal oxygen molecule is constituted of two oxygen atoms and is thus chemically written as O2. Each oxygen atom has a nucleus and six electrons with one pair shared with another normal oxygen atom with six electrons to form a normal O2 molecule. In a superoxide molecule there is a seventh electron unpaired electron and an additional negatively charged elctron (in red in the diagram below). It cannot bind to with its oxygen atom electron neighbour so is “free”, to bind with whoever it likes.



So we have a promiscuous molecule.

The hydroxyl free radical is similar in concept.

They can be called Oxidants.

The superoxide free radical is deployed by the immune system to bind to and damage the DNA of invading micro-organisms, preventing them from replicating and thus finishing them off. But in the same way (see later) it can attack the DNA of the body´s own cells as can the hydroxyl free radicals.

I´ll come back to the free radicals later but will now move onto muscle … don´t we love them! We can walk, talk, run and … breathe because of muscle. Sexy biceps and thighs!


The Heart

There is an essential difference between leg, arm, cheek etc and heart muscle. The former react to stimulation from nerves (i.e. the nerve gives a tiny electric shock to the muscle which makes it move) whilst heart (or cardiac) muscles do it by themselves (more or less) without the help of nerves.

(see diagram below of normal muscle).

You can be totally paralysed with no signals from brain to nerves to muscles but your heart keeps working and you stay (miserably) alive!

However, heart muscle cells, in comparison with the other muscle cells, are distinctly lacking in protection from our promiscuous and aggressive free radicals. This protection is principally in the form of various enzymes – superoxide dismutase (happily known under the acronym SOD), catalase, glutathione peroxidase and glutathione reductase. Unfortunately, heart cells produce a lot less of these enzymes than regular muscle cells.

According to Wikipedia, an infected mouse with SOD production genetically inhibited, can die within 21 days of birth!

Enzymes

Nicotinamide adenine dinuclenotide (NADH) and Nicotinamide adenine dinuclenotide phosphate (NADHP) are enzymes produced in cells from Niacin (or Vitamin B3 – look at the ingredients of your multivitamins) with unique roles concerning energy production and DNA synthesis.

Part of the anthracycline accepts an electron from NADH or NADPH and becomes a free-radical which immediately passes that unpaired electron to molecular oxygen (O2) thus becoming the very harmful, free radical – superoxide.

To make itself more stable the free oxygen radical has to steal an electron from mitochondrial DNA (and I can see I will have to explain the difference between mitochondrial and nuclear DNA). Without that oxygen electron the DNA molecules are damaged and the cells cannot reproduce.

Eventually, this will lead to cell death and as the heart muscle cells don’t have much protection from free reductions.

Anti-oxidants

This is an easy bit. If the anthracycline-induced anti-oxidants or free radicals, are roaming around, then introduce something that acts faster to mop them up before they hit the mitochondrial DNA in heart muscle cells.

Unfortunately, it seems that naturally-produced anti-oxidants, such as vitamins A, C and E (present in foods, drinks and vitamin supplements), are not adequate to this task so stronger anti-oxidant drugs have been introduced.

However, that is but one mechanism by which anthracyclines can damage the heart … (to be continued).
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