Re: Fwd: Results of DNA damage Tests, JCO criticality accident, Refs.

["Bjorn Cedervall" <bcradsafers@hotmail.com>]

>While I am not surprised, does anyone have a reference to confirm >that 
>"such results can also be obtained from tests on cigarette >smokers."

What is referred to is probably 7,8-dihydro-8-oxoguanine (8-oxoG), 
7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) or 8-Hydroxydeoxyguanosine 
(8-OHdG). These/this substance/s has/have been studied for a long time as 
biomarkers including in urine. Guanine (the base) reacts very readily with 
free radicals and alkylating agents at about 4-5 different sites. DNA in 
general contains many nucleophilic centers. These can donate electrons and 
therefore react readily with electrophilic compounds including alkylating 
agents like dialkylnitrosoamines, epoxides and others. In 1975 I worked with 
guanine reaction products (the O-6 and N-7 atoms - this is very different 
from the C-8-atom since reactions with the latter break up a double bond). 
For details regarding the C-8 atom I would recommend a contact with Peter 
Svoboda or Mats Harms-Ringdahl (Univ. Stockholm) who work in the field - 
they also had a recent paper in Radiat. Res.
Much about the organic/physical chemistry, and some of the biochemistry, was 
understood already then - it was also about that time (1972?), that it was 
found (by T. Lindahl and perhaps a few other people) that there is a high 
degree of spontaneous base loss in every cell every days (at least the order 
of 10 000 per day).

Guanine is quantitatively, but not necessarily from a mutational aspect, the 
most important of these bases lost spontaneously. Any reaction products 
(adducts) with guanine makes the structure more instable - the positions 7 
(nitrogen) and 8 (carbon) are perhaps the most critical in this sense. The 
oxygen on the 6 position is outside the ring system but an alkylation there 
will lock the electron resonance structure in the enol form (as opposed to 
the keto) and cause two of the three hydrogen bonds to disappear. The 
oxidation products like 8-OHdG and also other oxidized base products are to 
some degree extreted (urine) which probably is not the case with bases that 
just hydrolyzed spontaneously (without any attack from free radicals or 
alkylating agents).

The degree of alkylation/oxidation reactions interfering with the resonance 
structure of the 5-ring (3 carbons and 2 nitrogens) is probably inhibited by 
a high degree of anti-oxidant intake (eat a variety of vegetables!). If I 
recall correctly (some annual report from the NY Academy of Sciences around 
1975?), it was shown that smokers "use up" the vitamin C they take in - to a 
higher degree than non-smokers. About the same time, there was also a report 
showing that rats given nitrosoamines (or a precursor - can't remember) with 
vitamin C supplement had a much lower level of dialkyl-nitrosoamines 
(probably the dimethyl) in their blood as compared with the rats that got no 
Vitamin C supplement. Anti-oxidants probably also
helps to protect us against free radicals (like the OH.). There has been 
some controversy also regarding the role of smoking, and gender  (again room 
for discussion of unequal risk factors) and the oxidation products formed - 
it is not my major field nowadays but I have seen some reports while 
browsing for other topics.

So what is all this saying? That among the relevant factors for the 
formation of DNA breakdown products are probably smoking and food habits 
(nitrites in foods! The strongest correlator BTW with childhood leukemia I 
have seen in an epidemiological study (1994?) is the hot dog consumption 
among Californian children - a six-fold increase for those having at least 
12 hot dog meals per month - this is not saying that hot dogs is the _cause_ 
(there are now reports indicating that many of childhood leukemias may start 
as molecular biology phenomena at the fetal stage)).
To the possibly relevant factors for DNA base breakdown products in urine 
may be added age - I think that there are reports "out there" saying that 
the levels of guanine/guanosine breakdown products in urine due to oxidation 
of the 8-carbon (like those mentioned above) increase with age.

Litterature: I would search in Medline for articles in journals like 
Mutation Research, Environmental and Molecular Mutagenesis, Carcinogenesis, 
IJRB, Radiat. Res., E. Friedberg's books on DNA repair and probably many 
other books.

I represent myself in the reflections above - please comment or correct 
whatever may be relevant.

Bjorn Cedervall   bcradsafers@hotmail.com
Med. Radiation Biology & Med. Radiation Physics,
Karolinska Institutet, Box 260,
S-171 76 Stockholm, Sweden

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