Tuesday, August 2, 2011

Chromium 3 results in permanent modification to DNA in MoM hip? (4 and 5 of 6.) What does this mean?

I would like to understand what it means when they say that "direct binding of Cr3 to DNA is well documented" and why this matters to us as patients.

  • Wolf et al 1989 (done in prior post)
  • Landon et al 2004
  • Bacon et al 1983
  • Martnett et al 1999
  • Hartwig et al 2003
  • Witkiewicz-Kucharczyk and Bal 2006
I will explore this in a series of 6 posts.

Metal induced  intracellular effects:

In the two articles below, you will see that in cells, 2 main processes exist to correct DNA aberations.  Under similation by Chromium 6 and Cobalt, both of these repair mechanisms are inhibited.  So the metal causes the permanent damage in the DNA but the repair mechnisms that would typically remidy the situation, don't work.

Toxicology. 2003 Nov 15;193(1-2):161-9.

Modulation of DNA repair processes by arsenic and selenium compounds.

Source

Institut für Lebensmittelchemie und Toxikologie, Universität Karlsruhe, Postfach 6980, D-76128 Karlsruhe, Germany. andrea.hartwig@chemie.uni-karlsruhe.de

Abstract

Nickel, cadmium, cobalt and arsenic compounds are well known carcinogens to humans and experimental animals. In addition to the induction of mainly oxidative DNA damage, they interfere with nucleotide and base excision repair (BER) at low, non-cytotoxic concentrations. In case of arsenic, an inactivation of DNA repair has also been observed for the trivalent and pentavalent methylated metabolites, with the strongest effects exerted by MMA(III) and DMA(III). As potential molecular targets, interactions with so-called zinc finger proteins involved in DNA repair and/or DNA damage signaling have been identified. For example, arsenite suppresses poly(ADP-ribosyl)ation at extremely low, environmentally relevant concentrations. Also, Fpg and XPA involved in BER and NER, respectively, are inactivated by arsenite, MMA(III) and DMA(III). Nevertheless, an interaction with the zinc finger structures of DNA repair proteins may also occur by essential trace elements such as certain selenium compounds, which appear to exert anticarcinogenic properties at low concentrations but may compromise genetic stability at higher concentrations.


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Toxicol Lett. 2006 Mar 15;162(1):29-42. Epub 2005 Nov 28.

Damage of zinc fingers in DNA repair proteins, a novel molecular mechanism in carcinogenesis.

Source

Institute of Biochemistry and Biophysics, Polish Academy of Science, Pawińskiego 5a, 02-106 Warsaw, Poland.

Abstract

Zinc finger motifs participate in protein-nucleic acid and protein-protein interactions in many groups of proteins, including those involved in DNA repair. The Zn(II) ion, bonded tetrahedrally to cysteine thiolates and/or histidine imidazole groups, maintains the three-dimensional structure, crucial for the function of the domain. Zinc fingers can thus be compromised by a substitution of Zn(II) with another metal ion or by a release of Zn(II), due to the oxidation of thiolate donors. The latter may result from an action of redox-active metals or other oxidative agents. Studies in cell cultures and ex vivo demonstrated that soluble compounds of definite carcinogenic metals and metalloids, such as arsenic, cadmium and nickel, and putative carcinogens, including cobalt and lead, inhibit zinc finger containing DNA repair proteins. Further experiments demonstrated that these metals, as well as endogeneous oxidative substances, including hydrogen peroxide, nitrosoglutathione, and reducible selenium compounds damage or distort zinc finger domains. This reactivity can therefore be regarded as a novel molecular mechanism in carcinogenis.

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