A big opportunity in diagnostics: whenever there are huge ranges in the amount of a mutagenic analogue in DNA, there are probably several smaller and controllable factors behind it, besides obvious but smaller genetic differences. Consider the case of m1G – a tricyclic analogue of Guanosine formed by reaction of malondialdehyde with dG in DNA. In bacteria, this adduct is mutagenic if not repaired by nucleotide excision repair. The adduct may contribute to the etiology of cancer in humans. But even if m1G is not carcinogenic in humans, it still could be an important marker for fixable lifestyle problems. If m1G is not carcinogenic, then let’s find one that is. Same idea, same process, different marker.
DNA analysis indicates a 120 fold range in levels of this one adduct, person to person, an adduct that is normally repaired and should be readily detectable by HPLC-mass spec in urine, where it will be concentrated vs plasma by approximately the glomerular filtration rate, after further in vitro concentration.
Because the harmful DNA adduct is so low in concentration, it may be easier to measure the concentration of 4-OH-nonenal [4NE] (and malondialdehyde and methylglyoxal) in urine because 4NE seems to be hormetic in cells up to about 5 micromolar, but harmful above 10 micromolar – the compound should be readily quantifiable in urine with any kind of reasonable plasma concentration in “equilibrium” with tissue concentrations.
Detecting adducts like m1G in DNA has the advantage of being a look at it where it will do the most damage. Detecting such adducts in urine is a little ambiguous in that those who do not repair it well will have lower urinary adducts than those producing the same amount of it. Nevertheless, low DNA levels and low urinary levels are the clearly desirable outcomes of any efforts to minimize the damage to DNA. If the 120x differences person to person are solely due to genetic differences, then until we have means to fix mutations in vivo, the research will not lead to much. But if lifestyle variables like diet (many variables – what one is eating, high fat or sugar vs not, processed foods vs whole foods, organic vs not, and diet format: one meal vs three meals plus snacks, etc.), supplementation (not just antioxidant vitamins and nutrients but normal non-antioxidant biochemical compounds [like arginine] that will react with malondialdehyde and the like), fasting, etc., have a lot to do with the variation in levels of adducts like m1G, well there is a significant opportunity.
A study that attempts to convert those with high urinary levels of m1G into low urinary levels could be done. The same urinalysis can be used to eliminate those from the study who are not taking the supplements or have not made the dietary changes. The same urinalysis can be used to show significant improvement in those who have changed their lifestyle. Correlate these finding with cancer later in life and wow!
What are we waiting for? What an opportunity to make a difference!
Here is a relevant abstract re this important topic:
Mutat Res. 1999 Mar 8;424(1-2):83-95.
Lipid peroxidation-DNA damage by malondialdehyde.
- 1A.B. Hancock Jr. Memorial Laboratory for Cancer Research Center in Molecular Toxicology, Vanderbilt Cancer Center, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville TN 37232, USA. firstname.lastname@example.org
Malondialdehyde is a naturally occurring product of lipid peroxidation and prostaglandin biosynthesis that is mutagenic and carcinogenic. It reacts with DNA to form adducts to deoxyguanosine and deoxyadenosine. The major adduct to DNA is a pyrimidopurinone called M1G. Site-specific mutagenesis experiments indicate that M1G is mutagenic in bacteria and is repaired by the nucleotide excision repair pathway. M1G has been detected in liver, white blood cells, pancreas, and breast from healthy human beings at levels ranging from 1-120 per 108 nucleotides. Several different assays for M1G have been described that are based on mass spectrometry, 32P-postlabeling, or immunochemical techniques. Each technique offers advantages and disadvantages based on a combination of sensitivity and specificity. Application of each of these techniques to the analysis of M1G is reviewed and future needs for improvements are identified. M1G appears to be a major endogenous DNA adduct in human beings that may contribute significantly to cancer linked to lifestyle and dietary factors. High throughput methods for its detection and quantitation will be extremely useful for screening large populations.
Copyright 1999 Elsevier Science B.V.