Fluoroquinolones and DNA Adduction

There has been some controversy lately surrounding the possibility of the Fluoroquinolones (FQs) adducting to DNA.  I have been asked several times recently to weigh in with my opinion on DNA adduction as it relates to the FQs as 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 clear information that is backed up by science. This area is not one that is routinely research nor is it 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 do basically understand the science behind adductions, I have been opposed to some ways it has been presented to the community that resulted in fear.

Setting the fear aside, when I undertook my investigation I was prepared to deal with whatever I found, to ignore personal belief on the matter, and just deal in the facts.  A word of caution, this subject can be sobering. Although I do not believe this area is as harsh as some have made it to be, some of information may prove too sobering for some individuals. It is possible to misconstrue some of the science, and many do.  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.

Some Back Story…

Some people deeply desire to answer the one ‘Holy Grail’ question: “What is the mechanism that creates the Fluoroquinolone adverse reaction?” Those that know me know that I have a special interest in the long term chronic Fluoroquinolone adverse event.  Selfishly,, it is because I suffer from such an adverse events and I maintain friendship and correspondence with many people who have been dealing with these very adverse events for many, many years, some 20 to 25 years.

Over the years, there has been intense debate in the physiological causes of Fluoroquinolone toxicity.  I admit my opinion has vacillated due to the complexity. I believe there are many symptoms and many paths that one can follow after the initial insult, and I also believe there can be several paths, or series of conditions that lead up to the ‘big bang’ moment.  For many there are subtle changes on the cellular level that set the stage for the adverse event and once initiated, and based on the polymorphic uniqueness of individual physiology, results in varying levels of a cascading reaction. This uniqueness is a complex stew, influenced by genetic variations and environmental pressures, influence PH levels and trace elements.  These combinations are as unique as your fingerprints.  Then, once initiated, your unique physiology results in an almost infinite level of directions that the Fluoroquinolone adverse event can take.  Again, the variables are so complex that it can boggle the mind like a revolving Rubik’s cube puzzle. 

Although some adverse vents are quite similar, no two people are exactly alike nor do any two people have completely identical outcomes.  Find me two people with very similar adverse events and I will find you ten that are completely different. That is why it is terribly unfair, and unwise, to attempt to project your adverse event symptoms onto someone else or to attempt to ‘predict’ your outcome from someone else’s, even though it is in our psychological nature as humans to do so.

I have been blessed to interact with several researchers and many talented citizen scientists from the community you have to keep in mind that many root causes have been researched and dismissed, such as DNA transcription errors, MTHFR, G6P, blood type, and on and on. Although limited, there are researchers that continue to toil and focus on different pathological areas in an attempt to elucidate important clues.  Still, these are still downstream issues, and to this day well-intentioned and well-versed researchers have posed many theories but no one has come up with the “one” answer.  One of these theories in the ‘adduction’ theory. 

Adduction

DNA adducts are modifications of DNA that result from exposure to specific carcinogens.  The level of DNA adducts in normal cells can serve as a biomarker for a significant exposure to carcinogens. Adducts, that are not removed by the cell, can cause mutations that may give rise to serious health consequences.

It has been theorized that DNA adducts are solely responsible for Fluoroquinolone toxicity.   This theory, which was put for in a highly controversial and colorful manner to the community, has garnered both high criticism and high favor.  I will not wade into the personal controversies here. 

It is already a known fact that external toxins such as chemical agents can decompose and have compounds that cleave or adduct to  DNA.  One such infamous agent from the recent past was Agent Orange, used in Vietnam.  Other 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 [1].  However, 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 [2].  In 1993 the American Society for Microbiology published a paper on dealing enzyme mediated quinolone cleavage in vitro [3]. 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 [4]. 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 Fluoroquinolone sufferers and most physicians would not suspect, or even think, to pursue adduct testing, but should they? 

Let’s pursue this a bit further.

Complex Equipment Needed

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 damage. However, they cannot usually 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 mass-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.

Should We Be Concerned?

When the talk of DNA adductions starts floting around, especially on social media, many people end up viewing DNA adductions as a death sentence, or, at the very least, get real concerned.  I can understand why this information would cause worry, since no one wants mutated DNA hanging around in their body, however one must understand the variables involved.   If every individual that took a Fluoroquinolone experienced DNA adductions (and I doubt they do), the level of adducts that an individual would experience would be variable based on many factors, one of which includes the individual’s genetic polymorphisms that dictate DNA repair.  Because of this you cannot assume that everyone would have adducts or they would have the same level of adducts. This ‘varying levels of adduction based on a variety of factors’ is seen with other toxic substances such as hair coloring, fats, pesticides, tobacco, etc…

From past research on DNA adduction in cigarette smokers, adduction was neither uniform nor consistent across the smoking population.  In some smokers, DNA adducts resulting from cigarette smoke resulted in damage that manifested in different parts of the body, such as head neck, and bladder.   Again, logic would dictate that we would have to say that in Fluoroquinolone adduction DNA adducts would not be uniform and would would vary in intensity and location, if they appear at all.  This is due to a whole host of physiological factors including genetic variables for repairs, metabolism, enzymes, and co-factors (as indicated by the paper referenced earlier in this article).   

Bottom line…if everyone did have adducts, and again I doubt that this is true, we would see variations in the amounts of adducted material, varying locations, and they would not remain consistent.   Let’s remember that….

Adductions Are Not Pretty But Not That Rare

My goal here is to dissuade the level of fear and 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 an adverse event 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.

However if you won’t take my word for it, take the word of someone who is infinitely smarter than I am, someone who I have had the pleasure to briefly work with in the area of Fluoroquinolone toxicity. 

Dr. Mark Noble PhD from the University of Rochester. is a pioneering researcher in the fields of stem cell biology and stem cell medicine who currently holds professorships in Genetics, Neurology, Neurobiology and Anatomy at U of Rochester School of Medicine. Dr. Noble , who is very familiar with chemotherapeutic drugs (he has done pioneering research on the toxicity of the cancer drug 5Fu) has done work for the Fluoroquinolone looking into the toxicity of Levaquin.   He is one of the smartest men I know. Seriously.

Dr. Mark Noble’s knowledge of oncology and his pioneering research in the fields of stem cell biology and stem cell medicine has made him familiar with DNA adducts, very familiar.  As matter of fact, DNA adducts are right up his alley, so to speak.  In a nutshell, Dr. Noble said that “adducts cannot explain all the symptoms we see in FQAD.”  You can read more about Dr. Noble here and here.   

If you are reading this and you smoke, or previously smoked, 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.  If you have used commercially based hair colorings, there is a chance you may have adduction.

However, 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 Fluoroquinolone Adducts 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.

Stay Calm

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 Fluoroquinolone 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