Wednesday, January 16, 2013

Genetic and Epigenetic Mechanisms in metal carcinogenesis (5 of x in a series)

This is a difficult piece to understand.  I am not a scientist but have done my best to suss out the messages.

Part One in the series can be found here:

Part Two can be found here:

Part Three: chromium 6 metabolism and DNA Damage:

Part Four: Chromium (Cr)-DNA Adducts:

Part Five: DNA Base Damage , Genomic Instability, Toxicity and Cr 6 carcinogenesis.

Some in vitro  testing has demonstrated that administration of Cr 6 to animals with different levels of ascorbate failed to induce the formation of the resulting chemical which is the most widely used indicator of oxidative insult on DNA.  Similarly, replicaion of Cr 6 treated plasmids in human cells generated no mutagenic event when Cr 3 DNA binding was prevented or disrupted.  However, it has been recently reported that Cr 6 reduction by ascorbate yielded significant amount of another by- product which showed the oposite to be true.  [ inserted by connie/note, this paper was written in 2008, 7 years ago.  New findings have surfaced of course  but I still think this review of Cr toxicity is important for the following reasons:

  •  Oxidative stress (causes and exacerbates cancer) is not the only issue with Cr.  There are other issues over and above oxidative stress such as epigenenetic changes and altered signalling that also contribute to cancer
  • Regardless of  when these articles are written,  carncinogenisis  is associated with Cr
  •  All Cr 6 converts to Cr 3 ( or so this article states) but  for some unknown reason, with the hip issue, the "market" continues to neglect the fact that Cr 3 was initially introduced as Cr 6 and it is the reduction of one form to another that seems to  cause the cancer related  problems.]

Cr 6 activated malignant process proceeds through a very different path than other cancers! [Interesting.]  The spectrum of mutagenic events is more consitent with mutator phenotype of tumor.*

*Cancer cells contain numerous clonal mutations, i.e., mutations that are present in most or all malignant cells of a tumor and have presumably been selected because they confer a proliferative advantage. An important question is whether cancer cells also contain a large number of random mutations, i.e., randomly distributed unselected mutations that occur in only one or a few cells of a tumor. Such random mutations could contribute to the morphologic and functional heterogeneity of cancers and include mutations that confer resistance to therapy.

The authors point out that one interesting feature of Cr6 associated cancers was the presence of instability  which indicates the complete loss of the ability to repair the mutation with one of the protiens (MMR.)  If there is no MMR, they can't correct for replication errors and the cells exhibit 100x times higher mutation rates in the genes.  The frequency of the mutagenic events is even greater in the areas of simple microsites.

In summary, the cromate- associated cancer cells express the mutator phenotype caused by the loss of the mutation avoidance system (MMR.)  Once the cells inactivate MMR, the subsequent acquisition of mutations in the critical growth-controlling genes is greatly accelerated since these cells maintain high rates of random mutagenesis and NO LONGER NEED CONTINUOUS EXPOSRE TO CR6 FOR ADDITIONAL MUTAGENIC EVENTS.

[Well this doesn't sound too promising as it looks as though even if Cr 6 is converted quickly to cr 3, once the body was exposed to it, and the mutagenisis starts , the mutagenic process continues when the source  (Cr6) is removed?  Yikes!...

Just to add insult to injury, I continue to hear...."this is all animal model stuff and not proven in humans."  Well, not according to this paper.  This paper refers to studies done on both animal and human cells and at the time, the absence of MMR eliminated the ability  of Cr -DNA adducts to inhibit cellular replication of Cr in Cr 6.  Further, the damage- promoting effects of MMR extended to the full range of Cr 6 concentrations from very low nontoxic to highly toxic doses. Not sure what dose of Cr from the hip is a problem.]

I wish some biochemist would read this and comment on whether I got all of this right.  It is very complicated and well beyond my knowledge base.

Very interesting information indeed.

The last post in this series will address the issue of Cr 6 as a co-carcinogen.

cells. ...[I will ask my oncologist to explain this and pass it on to you.]

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