Fluoroquinolones and DNA Adduction
There has been some controversy lately surrounding the possibility of the Fluoroquinolones (FQs) adducting to nuclear DNA. I have been asked several times over the last few weeks to weigh in with my opinion on DNA adduction as it relates to the FQs. This subject has sparked much fear and stress, as it is a relatively unknown subject that seems to have many negative overtones.
This is not the first time that the DNA adduction controversy has surfaced in the FQ community and it probably will not be the last. What compounds this issue is the lack of information. This area is not one that is openly researched nor understood by your average medical practitioner. However, this does not necessarily mean that there is a complete lack of information available on the subject.
Intrigued by the science, I decided to give the subject a thorough search to satisfy my own curiosity. Although I am not against the theory of adduction itself, I have been opposed to some ways it has been presented to the community that resulted in fear. Setting the fear aside, I was prepared to deal with whatever I found, to ignore personal opinion on the matter, and just deal in the facts. A word of caution, this subject can be sobering. Although I do not believe it is as harsh as some have made it to be, some of these facts may prove too sobering for some individuals. Also, it is possible to misconstrue some of the science. So if you are in a fragile state I recommend that you not read any further until you feel stronger. Please, if you do read it, make sure to read it in its entirety.
In my opinion, there is still one ‘Holy Grail’ question that begs to be answered: “What is the mechanism that creates the FQ adverse reaction, especially the long term reactions?” Those that know me know that I have a special interest in the long term chronicity of FQ reactions. I maintain friendship and correspondence with many people who have been dealing with FQ reactions for many, many years, some 15 to 20 years.
Over the years, some people have told me that they believe that there are many physiological causes of FQ toxicity. I do not believe so. I believe there are many symptoms and many paths that one can follow after the initial insult, but I still believe that there is a ‘mother of all’ causes. Either a ‘big bang’ moment or a subtle change on the cellular level that, once initiated and based on the polymorphic uniqueness of individual physiology, results in varying levels of a cascading reaction. This uniqueness is a complex mix of enzymes, influenced by genetic variations and external pressures, plus varying levels of trace elements. These combinations are as unique as your fingerprints. Once initiated, your unique physiology results in an almost infinite level of directions that the FQ reaction can take. The variables are so complex that it boggles the mind. It is like a revolving puzzle. Although some reactions are similar, no two people are exactly alike nor do any two people have completely identical reactions. Find me two people with very similar reactions and I will find you ten that are completely different. That is why it is terribly unfair, and unwise, to attempt to project your reaction onto someone else or extrapolate your reaction from someone else, even though it is in our psychological nature as humans to do so.
I have been blessed to interact with many researchers and talented community folks working in areas of FQ toxicity. Many root causes have been researched and dismissed, such as DNA transcription errors. Even so, there are researchers that continue to toil and focus on different pathological areas such demyelination of nerve fiber, neuroendocrine dysfunction, and so forth. Although this research can elucidate important clues, these are still downstream issues. Obviously there are many opinions on this. Even well intentioned and well versed researchers have theorized as to the cause but no one has come up with the “one” answer.
It is already a known fact that external toxins such as chemical agents can decompose and have compounds that cleave or adduct to nuclear DNA. One such infamous agent from the recent past was Agent Orange, used in Vietnam. Things such as cigarette smoke condensates were initially known to have mutagenic activity by the 1970s, and adducts were detected in cellular DNA from smokers in the 1980s . Even certain fats, yes that’s right, fats, can, in certain cases, form adductions
So the million dollar question is, “can decomposed quinolone compounds adduct to nuclear DNA?” The answer is, yes. Researchers in 1992 in Italy found that decomposed compounds of norfloxacin could adduct to DNA and that the level of magnesium ions mediated, or controlled, the level of adduction that took place . In 1993 the American Society for Microbiology published a paper on dealing enzyme mediated quinolone cleavage in vitro . Again in 2009 Scientists in India reported on genotoxic and cytotoxic effects of the antibacterial drug, ciprofloxacin on human lymphocytes in vitro which involved DNA cleavage . There are more papers out there on the subject.
The problem with proving adduction for the average person is having the proper equipment to test for it. Most FQ sufferers and most physicians would not suspect, or even think, to pursue adduct testing. Now let me back up for a minute and discuss some basics of current testing.
Currently there are commonly used diagnostic laboratories that test for chromosomal abnormalities, DNA dysfunction, etc… These labs using the patient’s blood can check for the appearance of genetic mutations. Other labs check serum and/or urine to measure factors that indicate poorly functioning DNA by looking at downstream issues. A trained physician can use some of these tests to predict the likelihood that the patient quite possibly has DNA adduction. However, they cannot identify the actual adducting metabolized compounds. What is needed is a liquid chromatography – mass spectrometry machine.
LC-MS or preferably high performance (HPLC-MS) (mass-spec for short) is an apparatus for separating isotopes, molecules, and molecular fragments according to mass. It is needed to locate specific partially decomposed-metabolized components of the quinolones. If the adductions are there, these machines can locate them, provided you know where to look. So even if you have a mess-spec machine, you need to know where to look and what to look for. Preliminary tests should be run using interculating agents to identify binding properties of the quinolones and then locate binding sites. Once you know where to look, you have to find a mass-spec machine. Although getting more common, these machines are not readily available for public use. Many universities have these machines and also for-hire private labs. The cost for this type of testing can be quite expensive depending on the lab.
Getting a university to run such testing is a mixed bag due to the amount of drug company grants both direct and tacit. I won’t go into this directly, but I have seen certain requests for research denied based on that fact that the research is being done on a popular medication and the university did not want to jeopardize other grants. It is not impossible, just difficult, and it requires contacts.
Now many people view DNA adduction as a death sentence. I can understand why this revelation would cause worry, since no one wants mutated DNA hanging around in their body, however one must understand the variables involved. The amount of adduction in an individual is based on genetic polymorphisms in metabolizing pathways. This is an important determinant of DNA adduct levels. This ‘varying levels of adduction based on a variety of factors’ is seen in other areas, such as pesticides, tobacco, etc…
From past research on DNA adduction in cigarette smokers, adduction was neither uniform nor consistent across the individual. In some smokers, DNA adducts resulting from cigarette smoke resulted in a disease process more often in the lung, head and neck, and bladder. One would have to extrapolate this logic to FQ adduction and assume that adduction would not be uniform, would vary in intensity and location due to physiological factors such as genetic SNP’s for certain metabolizing pathways and even magnesium levels (as indicated by the paper referenced earlier in this article). This would easily explain why we see different areas affected in different people.
Modified DNA could present a wide range of symptoms from neurological manifestations, to mitochondrial dysfunction and many more. One might expect to see auto-immune mediated pathologies manifest themselves depending on the location, level of DNA modification, and condition of the immune system. However this area is one of great debate and much more research would be needed. Anyway, this could be one explanation of the wide array of symptoms that we see in FQ reactions.
Adductions Are Not Pretty But Not That Rare
My goal here is not to scare anyone, but to shed light on a difficult subject in an easy to understand manner. DNA adduction does not need to equate with a death sentence. Even if it is proven that everyone who has a reaction does, in fact, have varying degrees of adduction, there is still so much more we need to know. And there are many questions that cannot be answered by the DNA adduction theory alone.
If you smoke or smoked previously there is a chance that you have DNA adductions. If you have been exposed to strong pesticides, such as in the farming community, there is a chance you may have adduction. Not all DNA adduction leads to cancer or a slow disintegrating death. In many cases, the body has the ability to ‘heal’ adductions as was seen in some carcinogenic changes from cigarette smoking research. In the body, DNA Repair can happen at incredible speed under certain conditions.
In my opinion, right now, the only immediate positive result from finding out if one has a FQ adduction would be the peace that would come with knowing what the root cause is. I suppose for some it would initiate peace of mind, for others it might initiate more anxiety, worry, or worse. I would caution those from running right out and paying a large amount of money to find out if they have adductions or not. What will they do with the data? File a lawsuit? I doubt it. Even the ability to bolster an existing lawsuit would be highly doubtful. Right now the ability to provide adequate expert witnesses for DNA adduction in court would be a very astronomical task and extremely expensive task. Peer reviewed published papers would be necessary with university level research needed. For instance, a DNA adduction lawsuit would not be the same as providing the data and experts for tendon injury or even the current peripheral neuropathy warning issued by the FDA.
In reality, most doctors are still ill-equipped to handle such data, even if it is presented to them on paper. And, even if the doctor does believe you, what will he do with the data? The only thing he/she can do is, what a good mainstream doctor would normally do, treat you symptomatically. For the average floxed person, if the adduction theory proves correct, I am sure, sooner or later, certain labs will be identified where the cost for testing would be hopefully be reasonable, let’s say several hundred dollars, as opposed to several thousand dollars.
What needs to be done, if DNA adductions are proven to exist within the floxed community within a high percentage, is research on a treatment protocol to address all the downstream (ad hoc) issues.
Please do not let this subject become a knee jerk reaction leading to fear and extensive worry. There is much, much more that needs to be investigated on this subject and I am sure in the coming weeks and months more data will become known. However, just learning if adductions exist or not is not the end, just the opposite, it would open up a vast array of questions, resulting in the need for far more research. What needs to be avoided is the needless spreading of fear and trepidation from not having all the facts.
One final thought. Let me appeal to everyone’s ability for observational analysis. Everyone can make this judgment for themselves. Whether you are new to the FQ community or have been involved for a long time, take a moment, step back and view with your mind’s eye the community as a whole. What do you see? Does everyone have the same reaction? Does everyone that develops adverse events die? What about the fact that the community has a greater than 50% turnover rate yearly? If you are looking with an unbiased filter you will see a highly heterogeneous mix of results.
There may end up being one cause, but there definitely is not one destination.
Please read the sequel to this article: Hopeless or Hopeful? Fluoroquinolone and DNA Adductions Part Deux
1. L. D. Kier, E. Yamasaki, and B. N. Ames, “Detection of mutagenic activity in cigarette smoke condensates,” Proceedings of the National Academy of Sciences of the United States of America, vol. 71, no. 10, pp. 4159–4163, 1974.
2. Quinolone binding to DNA is mediated by magnesium ionshttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC50194/pdf/pnas01094-0315.pdf
3. Drug Features That Contribute to the Activity of Quinolones against Mammalian Topoisomerase II and Cultured Cells: Correlation between Enhancement of Enzyme-Mediated DNA Cleavage In Vitro and Cytotoxic Potential SARAH H. ELSEA,’ PAUL R. McGUIRK,2 THOMAS D. GOOTZ 2 MELINDA MOYNIHAN,2 AND NEIL OSHEROFFl* Department ofBiochemistry, Vanderbilt University School ofMedicine, Nashville, Tennessee 37232-0146,1and Department of Immunology and Infectious Diseases, Pfizer Central Research,Pfizer, Inc., Groton, Connecticut 063402
4. Genotoxic and cytotoxic effects of antibacterial drug, ciprofloxacin, on human lymphocytes in vitro PS Ambulkar,1 SK Ghosh,2 IV Ingole3 and AK Pal31Department of Biotechnology, Agnihotri College of Science, Wardha-442001, India 2Department of Anatomy, Nepal Medical College, Jorpati, Kathmandu, Nepal 3Human Cytogenetics Unit, Department of Anatomy, Mahatma Gandhi Institute of Medical Sciences, Sewagram, Wardha – 442102, India