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MDA and DNA Adducts
Biolab Medical Unit, UK
DNA Adducts
The levels of DNA adducts in human leucocytes has been found to vary with a number of lifestyle, environmental and
chemical-exposure factors. Increased dietary intake of antioxidants and essential metals,
especially zinc, are known to be protective.
Endogenous lipid peroxidation products such as malondialdehyde,
crotonaldehyde and 4-hydroxy-2-nonenal are particularly potent in forming adducts during periods of
oxidative stress. The type and quantity of fatty acids in the diet is also of
significance in that trans-fatty acids and their metabolic derivatives seem to lead to
excessive formation of adducts.
DNA adducts play a role in both vinyl chloride and urethane induced
tumorigenisis. DNA adducts are also implicated in many types of human cancer
especially where persistent oxidative stress leads to malignancy by increasing mutations and genomic instability at the
DNA level.
The detection of DNA adducts as pro-mutagenic markers enables, in some patients, an
understanding of cancer risk. It also defines and promotes active intervention measures
aimed at reducing exposure to the offending chemicals or moderation of the endogenous processes responsible for some
adducts. This is particularly so where the level of and destructive activity of metal adducts can be reduced by the use
of nutritionally important, essential metals such as zinc. Zinc normally plays a number of very important roles in the
cross-bridging of DNA and in the finger-proteins that are part of the process of reading the code.
Cancers with poorly defined etiology may be explained once DNA adducts are identified. And, this applies to the individual
patient not just to a research situation. That DNA adducts can both block anti-tumour genes and activate oncogenes is well
established.
Malondialdehyde is a naturally occurring product of the peroxidation of lipids and it is also
formed during the production of prostaglandins, prostacyclins and leucotrienes that are derived from the essential fatty acid
pathways. Malondialdehyde production is increased when trans-fatty acids are the starting point for some of these reactions that
would normally only involve the cis-fatty acids. Some workers have also suggested that malaondialdehyde levels are increased when
mono-unsaturated fatty acids dominate pathways that would usually only favour poly-unsaturates as their starting points. This is
still a matter of debate and research. However, it is clear that adequate availability of cis-polyunsaturated essential fatty acids
favours normal production and balance of prostaglandins without excessive formation of malondialdehyde. The
presence of adequate levels of antioxidants limits the damage to cell membrane lipids that is the major source of malondialdehyde
in most people.
Malondialdehyde reacts with DNA to form adducts to deoxyguanosine and deoxyadenosine. The major adduct
is a pyrimidopurinone known as M1G. Detailed studies of the adduct site-specific mutagenesis show
that this defect is sometimes repaired by the nucleotide excision enzymes but that pathway is itself heavily zinc-dependent. This
may mean that a person with poor antioxidant status who is also zinc deficient (a combination fairly
commonly seen in the test profiles performed in this Unit) could have a much higher chance of forming non-repairable
M1G DNA adducts.
There is now little doubt that M1G is a major endogenous DNA adduct that significantly contributes to cancers
that are linked to lifestyle and nutritional factors. M1G has been detected in leucocytes, liver, pancreas and breast tissue from healthy
individuals. The highest levels being found in those reasonably assumed to be in the highest cancer-risk categories. Studies are incomplete
with regard to what proportion of these people go on to develop malignancies but initial evaluation suggests that it is of the order of 40%
M1G is not the only malondialdehyde-DNA adduct but it is (to-date, 2002) the most fully investigated. Other adducts include M2G,
M1dA, M3dA, M1dC and M3dC each of which can lead to mutagenesis and promote malignancies. The identification
of these in human genomic DNA has, until recently, depended on 32P postlabelling techniques and mass spectrometry methods that are limited to
research applications. We have recently published a peer-reviewed method that opens up the detection of these and other DNA adducts in peripheral
leucocytes from clinically relevant blood samples. Although it has not been done at the time of writing, this technique could easily be extended to the
detection and quantifying of DNA adducts in other tissues (eg. from simple needle biopsy).
In 1996, it was reported that M1G is 2-to-3 times higher in normal breast tissue from patients with breast cancer
than in similar tissue from women without breast cancer. The levels of M1G in the tumour tissue is lower than in the surrounding normal tissue.
The ratio being an indication of the aggressiveness of the malignancy. An aggressive tumour that is from a fast growth mutation would not be
expected to have significant levels of M1G while the M1G in the surrounding tissue would be at high level when malondialdehyde-related adducts
were a significant factor in the etiology. This would give a high ratio of M1G-normal tissue-to-M1G-tumour tissue. A slow growing tumour might be
expected to have a somewhat higher level of M1G but whether it does or not the level of M1G in the surrounding tissue would be lower. This would
give a lower ratio of M1G-normal tissue-to- M1G-tumour tissue than for an aggressive malignancy. Such assessments may prove valuable in the choice
of treatment.
Biolab Medical Unit, a medical referral laboratory specialising in Nutritional and Environmental Medicine, is located in the heart of
the West End of London.
Biolab is a nutritional biochemistry laboratory measuring vitamin and mineral levels, toxic metals, other biochemical levels that are related to the
availability of vitamins, minerals and other nutrients, and also have an extensive range of profiles for assessing the effects of twenty-first century
lifestyles on our bodies.
Free Radicals Test kit - colour chart
The above information is provided for general
educational purposes only. It is not intended to replace competent
health care advice received from a knowledgeable healthcare professional.
You are urged to seek healthcare advice for the treatment of any
illness or disease.
Health Canada and the FDA (USA) have not evaluated these
statements. This product is not intended to diagnose, treat, cure, or prevent
any disease.
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