Tuesday, January 8, 2013

Genetic and Epigenetic Mechanisms in metal carcinogenesis (3of x in a series)


Part One in the series can be found here: http://www.mydepuyhiprecall.com/2013/01/genetic-and-epigenetic-mechanisms-in.html

Part Two  in the series can be found here:http://www.mydepuyhiprecall.com/2013/01/genetic-and-epigenetic-mechanisms-in_7.html

Part Three: chromium 6  metabolism and DNA Damage:

1.  Carcinogenic metals are typically weak mutegens and with the exception of chromium (Cr), they do not form DNA adducts which represent a key initiating event in the cancer -inducing activity of organic carcinogens.

2.  Although Cr can exist in several valence states, the most commonly encountered products contain  this metal in the 6, 3 and zero states.

3. Cr 3 is the final oxidative form found in all biological systems. [ note from connie: Cr 6 is known to be toxic.  Cr 3 is not. Cr 3 is what is claimed to be in the Depuy hip............after it is oxidized from Cr 6.  it would certainly be correct to state that Cr3 is found in the depuy hip but it would not be correct to assume it was Cr 3 to start with.  Cr 6 is oxidized to Cr 3.]

4.  Cr 6 can readily enter cells.  A 24 hour long incubation can lead to 100 fold or higher accumulations.

5.  Cr 6 is a procarcinogen that by itself is completely unreactive toward DNA under physiological pH and temperature.

6.  In the biological systems, however, Cr 6 undergoes a series of reduction reactions yielding thermodynamically stable  Cr 3. [ note from connie:  so, as a result of this, consumers of this information seem to conclude that there is no issue.  Not so. the next point is critical.]   BUT

7.  Inside the cell, Cr 6 reduction is the activation event that is responsible for the generation of genotoxic damage and other forms of toxicity.  Unlike the majority of other human pro-carcinogens, Cr 6 metabolism in mammalian cells does not require any enzymes and relies on the direct electronic transfer from ascorbate and non protein thiols such as glutathione and cysteine.

8.  Ascorbate is the dominant biological reducer  of Cr 6.   Unless Ascorbate levels are restored to normal, typical cell cultures  provide a nonphysiological model of Cr 6 metabolism which has recently been found to underestimate the genotoxic and mutagenic abilities of Cr 6.

9.  The end-product of Cr 6 metabloism in all biological systems is always Cr 3 BUT the reduction process can also generate variable amounts of Cr 5 and Cr 4 and organic radicals.

10.  studies of Cr 6 treated cells produced evidence for the formation of several types of DNA damage including strand breaks and various Cr -DNA adducts. (more on what this is and why it matters in the next series.)

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