Tag Archives: enzymes

Persistent Fluoroquinolones in the Body and Delayed Adverse Reactions

This is a guest post written by Gary. You can read Gary’s story HERE. It contains a wonderful wealth of knowledge, insight, and advice. 

Fluoroquinolone side effects are often multisymptom affecting a wide range of bodily functions, ie: CNS, Muscles, Tendons, Brain, etc (Halkin, 1988l Mattappalil and Mergenhagen, 2014; Menzies et al., 1999; Moorthy et al., 2008; Thomas and Reagan, 1996; etc)

The chronic, often multisymptom, effects are not well documented and are normally assigned (often multiple) different diagnosis by doctors, such as clinical depression, fibromyalgia, etc/ (Strauchman and Morningstar, 2012)

I argue the reason for the chronic effects is because the Fluoroquinolones are not metabolized correctly, or the are metabolized and the normal biological enzymes that are responsible for detoxification of xenobiotic substrates is impared. A xenobiotic is a synthetic chemical such as Levaquin, Cipro, pestacides, etc. It’s also likely that FQ exposure changes gene expressions relating to various cytochrome P-450s (which is responsible for metabolizing and detoxification) causing your body to accumulate toxic chemicals, being unable to remove them.

For example, According to Liang et al., (2015), Fish that were exposed to a specific FQ had changes to cytochrome P450 1A (CYP1A), cytochrome P-450 3A (CYP3A), glutathione S-transferase (GST), P-glycoprotein (P-gp), which are all responsible for metabolizing and/or removal of xenobiotics. Other animals exposed to FQs were shown to have changes in cytochrome P-450 sites – For example, Dogs exposed to FQs showed inhibiting only cytochrome P-450 3A (Regmi et al., 2005; 2007), Chickens (Shlosberg et al., 1997; Granfors et al., 2004). To be fair, this might not affect humans completely, but this would likely explain the delayed toxicity to the CNS and other parts of the body – Delayed toxicity for FQ patients are likely a result of impared detoxification pathways due to FQ exposure overall which means the body has a high level of xenobiotics that cannot be removed.

There are even a few case studies on /people/ to support this article. In a paper (Strauchman and Morningstar, 2012), a patient was prescribed Moxifloxacin in 2005 and developed a worsening set of symptoms (after inclusion of medication), such as episodic tachycardia, episodic dizziness, episodic shortness of breath, and chronically swollen glands. Additional symptoms included daily episodes of nausea, sweating, tremors, brain fog, blurred vision, panic attacks, and phonophobia. Over the course of 3 years, after Moxifloxacin treatment, her condition improved, modestly.

In 2011, the PCP diagnosed the patient with diverticulitis and prescribed her ciprofloxacin 500 mg – Over the course of the treatment, she started to experience all the previous symptoms from 2005 – including panic attacks, insomnia, blurred vision, tachycardia, and nausea. This episode additionally included diffuse musculoskeletal joint pain. The patient also reported that her elbows, wrists, and knees seemed to crack too easily and too often. (p.3). Full workup was ordered, including genetic testing which showed the following:

– Genetic polymorphism in the cytochrome P-450 pathway

– Genetic variations in the catechol-o-methyl transferase enzyme, the Nacetyl transferase enzyme, and the glutathione-s-transferase enzyme necessary for glutathione conjugation and phase II detoxification.

The patient was also tested for polychlorinated biphenyls and other volatile solvents. They found the patient to have elevated levels of ethylbenzene, xylene, and the pesticide dichlorodiphenyldichloroethylene. Although these levels could indicate environmental accumulation, impaired detoxification pathways may make this accumulation more of a contributing factor.

Fluoroquinolone treatment seems to affect enzymes possesses, causing reduced activity due to chelation of ions, such as Se2 [Selenium], Mg2 [Magnesium], Fe2/3+ [Iron] (Badal et al., 2015; Uivarosi, 2013; Seedher and Agarwal, 2010) which explains the chronic issues, as well as delayed toxicity (due in part to impaired detoxification)

Even more evidence that either FQs remain in the body, impairing detoxification of xenobiotics (or they contribute to impairment) is from a journal (Cohen, 2008) where a patient was on a 14 day course of Moxifloxacin and became disabled, for many years; His symptoms were Brain Fog, Cognitive Defects/memory loss, tingling and numbness in his legs, joint pains, Achilles pain, Chronic Fatigue, Weakness, to a degree that he could barely stand or walk; The patient began IV Based Antioxidant therapy, and his condition improved considerably (95%+ recovery within a month). It’s highly likely that the IV Antioxidant therapy activated/modulated cytochrome P-450 to allow the patients body to excrete the excessive, normal environmental xenobiotics (and including Moxifloxican) and the patient recovered.

Fluoroquinolones have a very high melting point, over 200C, which means the crystals they form are very stable in neutral pH. (Andriole et al., 2000). If FQs are stuck within the cells, then that means they are responsible with mitochondrial ETC leakage, causing depressed health effects (ie: Brain Fog from FQ exposure is likely caused by FQs interfering with ATP energy output, which affects the Brain’s homeostasis).

What causes the delayed toxicity? There are only 3 possible explanations.

– You have pre-existing genetic polymorphisms in cytochrome P450s (and others) that prevent you from metabolizing and/or excreting FQs – Which leads to various normal systems in the body to suffer for a long period of time. (FQ crystals are ‘stuck’ in your body)

– FQs /cause/ the polymorphisms because they chelate heavy metals that enzymes require for proper biological function, such as phase II detoxification. Once this happens, your body begins to accumulate xenobiotics and you develop delayed toxicity.

– FQs cause mitochrondia dysfunction with organs responsible for generting glutathione, causing your body to have extremely low levels of glutathione, leading to increased amounts of xenobiotics that you cannot remove.

If this behavior takes place, how do we prove it?

– Genetic testing is the only way to be sure you have these Genetic polymorphisms/Genetic Variations – Some sites out there do provide this.

– Liquid Chromatography-tandem mass spectrometry will need to be performed on blood samples from people currently damaged by FQs to see if any concentrations of it exist in plasma.

– Total GSH testing would likely show lower-than-expected glutathione levels in the body with someone that is disabled, because if FQs are embedded in the cells, they are likly decreasing ATP output of various organs.

How would we remove the FQs that are ‘stuck’ in the body?

– Ozone is able to remove FQs from water (Feng et al., 2016). Therefor, Ozone therapy might be an idea If this behavior of FQs takes place.

– Fluoroquinolones have a Michael acceptor in them, making them very electrophilic. The non-aromatic double bond could potentially be subject to nucleophilic attack via a Michael addition, so one removal strategy could be allowing ligating the fluoroquinolone/associated polymorphs to something that is readily transported across cell membranes and excreted. However, this would need to be drawn up on a computer simulation to see if this could be done, cost effectively.

– Prolonged IV Antioxidant therapy, as shown above, seems to reverse FQ toxicity in some patients but further testing will need to be done (A heavy metal toxscreen via blood to be tested for chemical insult will likely need to be ordered)

Pharmacogenomics is going to likely show who is compatible with FQs and who isn’t, down the road–once we identify specific SNP’s that are broken with us floxies, the /good/ news is, with CRISPR technology, those of us with pre-existing polymorphisms (pre/post-FQ) will likely be able to have them corrected with little to no side effects.

Data from the following:

Strauchman M, Morningstar MW. Fluoroquinolone toxicity symptoms in a patient presenting with low back pain. Clinics and Practice. 2012;2(4):e87. doi:10.4081/cp.2012.e87.

N. L. Regmi, A. M. Abd El-Aty, R. Kubota, S. S. Shah, and M. Shimoda, “Lack of inhibitory effects of several fluoroquinolones on cytochrome P-450 3A activities at clinical dosage in dogs,” Journal of Veterinary Pharmacology and Therapeutics, vol. 30, no. 1, pp. 37–42, 2007.  ·  ·

N. L. Regmi, A. M. Abd El-Aty, M. Kuroha, M. Nakamura, and M. Shimoda, “Inhibitory effect of several fluoroquinolones on hepatic microsomal cytochrome P-450 1A activities in dogs,” Journal of Veterinary Pharmacology and Therapeutics, vol. 28, no. 6, pp. 553–557, 2005.  ·  ·

M. D. Brand, R. L. Goncalves, A. L. Orr et al., “Suppressors of superoxide-H2O2 production at site IQ of mitochondrial complex I protect against stem cell hyperplasia and ischemia-reperfusion injury,” Cell Metabolism, vol. 24, no. 4, pp. 582–592, 2016.  ·  ·

M. A. Simonin, P. Gegout-Pottie, A. Minn, P. Gillet, P. Netter, and B. Terlain, “Pefloxacin-induced Achilles tendon toxicity in rodents: biochemical changes in proteoglycan synthesis and oxidative damage to collagen,” Antimicrobial Agents and Chemotherapy, vol. 44, no. 4, pp. 867–872, 2000.  ·  ·

Krzysztof Michalak, Aleksandra Sobolewska-Włodarczyk, Marcin Włodarczyk, Justyna Sobolewska, Piotr Woźniak, and Bogusław Sobolewski, “Treatment of the Fluoroquinolone-Associated Disability: The Pathobiochemical Implications,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 8023935, 15 pages, 2017. doi:10.1155/2017/8023935

J. M. Radandt, C. R. Marchbanks, and M. N. Dudley, “Interactions of fluoroquinolones with other drugs: mechanisms, variability, clinical significance, and management,” Clinical Infectious Diseases, vol. 14, no. 1, pp. 272–284, 1992.

H. H. M. Ma, F. C. K. Chiu, and R. C. Li, “Mechanistic investigation of the reduction in antimicrobial activity of ciprofloxacin by metal cations,” Pharmaceutical Research, vol. 14, no. 3, pp. 366–370, 1997.

N. Seedher and P. Agarwal, “Effect of metal ions on some pharmacologically relevant interactions involving fluoroquinolone antibiotics,” Drug Metabolism and Drug Interactions, vol. 25, no. 1–4, pp. 17–24, 2010.

H. Koga, “High-performance liquid chromatography measurement of antimicrobial concentrations in polymorphonuclear leukocytes,” Antimicrobial Agents and Chemotherapy, vol. 31, no. 12, pp. 1904–1908, 1987.

A. Pascual, I. García, S. Ballesta, and E. J. Perea, “Uptake and intracellular activity of trovafloxacin in human phagocytes and tissue-cultured epithelial cells,” Antimicrobial Agents and Chemotherapy, vol. 41, no. 2, pp. 274–277, 1997.

V. T. Andriole, The Quinolones – Third Edition, Acedemic Press, San Diego California, 2000.

S. Badal, Y. F. Her, and L. J. Maher 3rd, “Nonantibiotic effects of fluoroquinolones in mammalian cells,” The Journal of Biological Chemistry, vol. 290, no. 36, pp. 22287–22297, 2015.

J. Y. Lee, S. H. Lee, J. W. Chang, J. J. Song, H. H. Jung, and G. J. Im, “Protective effect of metformin on gentamicin-induced vestibulotoxicity in rat primary cell culture,” Clinical and Experimental Otorhinolaryngology, vol. 7, no. 4, pp. 286–294, 2014.  ·  ·

Z. K. Salman, R. Refaat, E. Selima, A. El Sarha, and M. A. Ismail, “The combined effect of metformin and L-cysteine on inflammation, oxidative stress and insulin resistance in streptozotocin-induced type 2 diabetes in rats,” European Journal of Pharmacology, vol. 714, no. 1–3, pp. 448–455, 2013.  ·  ·

A. I. Morales, D. Detaille, M. Prieto et al., “Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway,” Kidney International, vol. 77, no. 10, pp. 861–869, 2010.  ·  ·

W. Chowanadisai, K. A. Bauerly, E. Tchaparian, A. Wong, G. A. Cortopassi, and R. B. Rucker, “Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression,” The Journal of Biological Chemistry, vol. 285, no. 1, pp. 142–152, 2010.  ·  ·

T. Stites, D. Storms, K. Bauerly et al., “Pyrroloquinoline quinone modulates mitochondrial quantity and function in mice,” The Journal of Nutrition, vol. 136, no. 2, pp. 390–396, 2006.

Y. Huang, N. Chen, and D. Miao, “Biological effects of pyrroloquinoline quinone on liver damage in Bmi-1 knockout mice,” Experimental and Therapeutic Medicine, vol. 10, no. 2, pp. 451–458, 2015.  ·  ·

M. Feng, L. Yan, X. Zhang et al., “Fast removal of the antibiotic flumequine from aqueous solution by ozonation: influencing factors, reaction pathways, and toxicity evaluation,” Science of The Total Environment, vol. 541, pp. 167–175, 2016

**

Fluoroquinolones Deplete Iron and Lead to Epigenetic Changes

In my ciprofloxacin toxicity recovery story I note that:

I take a low dose iron supplement – only 5 mg. – daily. The brand of iron supplement that I use is Pur Absorb, but I’m guessing that other low-dose iron supplements will work equally well. Within just a couple days of starting taking the iron supplement, my energy levels increased dramatically. I could walk a mile without being exhausted afterward. In addition to improving my energy level, the iron supplement seems to make my muscles and tendons more supple and malleable. When my tendons are feeling tight, a dose of iron helps to loosen them up – within just a couple hours. Too much iron is really bad for you, so please be careful with supplementing it (ask your doctor, yada yada), but it helps me immensely.”

I’ve always wondered why iron helped me to recover from fluoroquinolone toxicity. In some ways, it didn’t make sense – iron is an oxidant (according to a doctor friend, it’s a bit more complicated than that, and in some situations iron can be an antioxidant and in others it can be an oxidant), and antioxidant supplements are what help most floxies. Also, iron is a component of the Fenton Reaction, and the Fenton Reaction is where, “Iron(II) is oxidized by hydrogen peroxide to iron(III), forming a hydroxyl radical and a hydroxide ion in the process. Iron(III) is then reduced back to iron(II) by another molecule of hydrogen peroxide, forming a hydroperoxyl radical and a proton. The net effect is a disproportionation of hydrogen peroxide to create two different oxygen-radical species, with water (H+ + OH–) as a byproduct.” Basically, iron can “donate or accept free electrons via intracellular reactions and help in creating free radicals.” Free radicals are ROS. Some of the nastiest ROS are created in the Fenton Reaction – hydroxyl radicals and hydroperoxyl radicals. According to “Oxidative Stress Induced by Fluoroquinolones on Treatment for Complicated Urinary Tract Infections in Indian Patients,” fluoroqinolones increase the production of ROS, and it has been postulated (by myself and others) that the mechanism for fluoroquinolone toxicity is an excess of ROS wreaking havoc on all systems of the body.

So, why did iron make me feel so much better?

It’s a question that has perplexed me for years.

Answers to that question can be found in the article, “Non-antibiotic effects of fluoroquinolones in mammalian cells” which was published in the July, 2015 issue of The Journal of Biological Chemistry. In this post I will highlight some of the more interesting findings from “Non-antibiotic effects of fluoroquinolones in mammalian cells.” All excerpts from the article are quoted and italicized.

Here we show that the FQ drugs Norfloxacin, Ciprofloxacin, and Enrofloxacin are powerful iron chelators comparable to Deferoxamine, a clinically-useful iron chelating agent.”

Fluoroquinolones suck iron out of (chelate) cells just as well as drugs that are meant to suck the iron out of cells (Deferoxamine). Iron is an essential mineral that is critical for transporting oxygen throughout the body. Chelation of iron from cells can be detrimental to health in multiple ways including, “delayed cognitive function, poor exercise performance and lowered immune function. In children, iron deficiency anemia can cause psychomotor and cognitive abnormalities resulting in future learning difficulties.

We show that iron chelation by FQ leads to epigenetic effects through inhibition of α-ketoglutarate-dependent dioxygenases that require iron as a co-factor.”

fluoroquinolone-lawsuit-banner-trulaw

Iron depletion leads to adverse epigenetic effects through inhibition of iron-dependent enzymes. This is a very big deal – Fluoroquinolones can change genetic expression (epigenetics) in human cells. Later in the article it is noted that, “This is the first study to show global epigenetic changes induced by FQ antibiotics.” It had been previously postulated in “Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology” (2009) that all fluoroquinolone adverse effects were the result of epigenetic changes, but “Non-antibiotic effects of fluoroquinolones in mammalian cells” describes the first study of human cells that shows epigenetic changes caused by fluoroquinolones. Epigenetics wasn’t even a notion, much less a field of study, when the FDA approved fluoroquinolones, drugs whose mechanism of action is, “inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.” Think about that next time you pick up a drug from the pharmacy and assume that it’s safe because the FDA approved it.

Dioxygenases are enzymes that are necessary for aerobic life. Fluoroquinolones inhibit α-ketoglutarate-dependent dioxygenases, which require iron as a co-factor.  Depletion of α-ketoglutarate-dependent dioxygenases leads to changes in how genes are expressed.

Fluoroquinolones were also found to inhibit several demethylases, “enzymes that remove methyl (CH3-) groups from nucleic acids, proteins (in particular histones), and other molecules. Demethylase enzymes are important in epigenetic modification mechanisms. The demethylase proteins alter transcriptional regulation of the genome by controlling the methylation levels that occur on DNA and histones and, in turn, regulate the chromatin state at specific gene loci within organisms.” FQs were found to inhibit “Jumonji domain histone demethylases, TET DNA demethylases, and collagen prolyl 4-hydroxylases, leading to accumulation of methylated histones and DNA, and inhibition of proline hydroxylation in collagen, respectively. These effects may explain FQ-induced nephrotoxicity and tendinopathy.” (emphasis added).

Many possible mechanisms for the tendinopathy and compromised collagen integrity caused by fluoroquinolones have been proposed. It has been suggested that fluoroquinolone caused destruction of connective tissues are due to metalloprotease (MMP) malfunctions, magnesium depletion, and the NO/ONOO cycle. In “Non-antibiotic effects of fluoroquinolones in mammalian cells” it is asserted that iron chelation, and the inhibition of enzymes that utilize iron, are behind the fluoroquinolone-caused musculoskeletal adverse effects:

These results suggest, for the first time, that FQ treatment can cause unanticipated epigenetic effects. Moreover, we suggest that the well-established linkage between FQ treatment and tendinopathy reflects impairment of collagen maturation by FQ. We suggest that it is the inhibition of collagen 4 prolylhydroxylases by FQ mediated iron chelation, and repression of collagen P4H1 and LH1 transcription that underlies the peculiar tendinopathy side effects of FQ antibiotics.”

And:

FQ are potent iron chelators capable of inhibiting 2-KG dependent dioxygenases because of the crucial role of iron in the active site. We show that FQ treatment inhibits collagen maturation. Prolyl 4- hydroxylase and lysyl hydroxylase are iron dependent enzymes essential for the post-translational modification of collagen. Both play central roles in collagen maturation through hydroxylation of proline and lysine residues to mediate collagen cross-linking. Covalent crosslinks are required for the tensile strength of collagen fibers (64). We suggest that it is iron chelation by FQ that accounts for suppressed collagen hydroxylation, giving rise to tendinopathies.”

And:

Additionally, suppression of HIF-1α can have drastic effects on vascularization and energy metabolism in connective tissues, contributing to decreased blood flow in an already hypoxic and avascular tissue. We suggest that these three insults – inhibition of prolyl and lysyl dioxygenases, reduction of P4HA1 and LH1 mRNA levels, and reduced tendon vascularization upon HIF-1α depletion – together account for FQ induced tendinopathies.”

To sum up the excerpts, fluoroquinolones chelate iron from cells, this leads to inhibition of iron-dependent enzymes, which lead to epigenetic changes that result in collagen malformation and tendinopathies. It should also be noted that fluoroquinolones chelate other minerals, including magnesium, from cells, and magnesium-dependent enzymes are inhibited by fluoroquinolones as well.

All doctors and researchers, and the FDA, should note that in chelating necessary minerals from the body, fluoroquinolones are not only inhibiting necessary enzymatic reactions, they’re also changing genetic expression, and that the long list of severe adverse effects of fluoroquinolones may be due to adverse expression of genes. Neither long-term, nor intergenerational effects of fluoroquinolones are currently known.

So… what should floxies do with this information? Personally, I supplement iron and I find that it helps me immensely. Not everyone can, or should, supplement iron though. Too little iron is bad, but too much is also harmful. The prudent thing to do is to get your iron levels tested and to supplement if necessary under the care of your doctor.

When I corresponded with Dr. Maher, one of the authors of “Non-antibiotic effects of fluoroquinolones in mammalian cells,” he noted that, “I would simply emphasize that what we demonstrate in this work involves human cells grown in culture, and lab conditions, and we want to make it clear that these are findings of potential mechanisms of fluoroquinolone antibiotics that could be relevant for patients, but we provide no direct data related to human patients or treatments. Further studies will be required to understand if these or related effects actually occur in people.”

I am thankful to Doctors Badal, Her and Maher for their work on “Non-antibiotic effects of fluoroquinolones in mammalian cells!” Of course, caution should be used when drawing conclusions from their results. Though I shouldn’t draw conclusions about how FQs react in a complex human body from how human kidney cells react in a petri dish, I don’t think that it’s completely out of line to say that the potential implications of this research are huge. The chelation of minerals from cells by fluoroquinolones may be leading to epigenetic changes in the people who take fluoroquinolones. What this means for their health is not currently known.

The epigenetic adverse effects of fluoroquinolones were found to be reversible by exposing the floxed cells to iron, and studies have shown that magnesium, vitamin E, MitoQ and NAC can reverse some of the effects of fluoroquinolones, so please have hope, hang in there, and take your mineral supplements (under the supervision of your doctor, yada, yada).

 

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