My hope is to fill this in with more details on the following mechanisms to consider for research. All of these are strong contenders on my list as unintentional targets of FQ’s. These listed areas of focus, with all their related cascade of mechanisms, probably encompass a million or more places to look for actual FQ binding and FQ induced damage, whether that’s genomically or metabolically. So I’m under no illusion that finding where the problem(s) are is simple. However, given the billions of places in the body for potential FQ induced damage to occur, this does narrow it down a bit, even if only to “ a million” places to look.
“Promiscuous Binding”: The concept of “promiscuous binding” is that many, if not all, of the drugs we take not only bind to their intended target, but to additional targets as well to some extent. In other words, FQ’s target not only the bacterial topoisomerase enzymes, but also are binding to human proteins as well or their intermediates. This includes not only the human counterpart topoisomerases, but other enzymes, receptors, transporters or proteins in the human body, which is why side effects of these drugs occur in some people. For people unfamiliar with biology or biochemistry, these proteins are also located and expressed throughout many cells and tissues of the body, which is another reason side effects occur. As one very simplistic example, specific ACh receptors are expressed and active in the brain, as well as in tendons, so any drug that binds to those particular receptors will affect both. Hormone and neurotransmitter receptors are involved in literally every function in the body, and due to Promiscuous Hormones and Other Fun Facts, is why endocrine and neurotransmitter disruption can have such widespread and devastating effects.
Steroid Super Family Receptors/ HRE’s (with a side of Neural Crest Cell Derivatives): I believe the FQ’s are severe endocrine disrupters, and these receptors and hormone response elements, or their common pathways, may be unintentional targets. I’ve discussed this concept several times throughout this document. As one example, the retinoid X receptors (RXR) serve as a common important partner for many other nuclear receptors, including thyroid hormone, Vitamin D/Calcitriol, Retinoic Acid (Vitamin A), Pregnane X/Steroid and Xenobiotic Sensing, Peroxisome Proliferator transcription factors for metabolism of carbohydrates, lipids, and proteins, Liver X regulators of cholesterol, fatty acid, and glucose homeostasis, Bile Acid receptors, and more. A quick look through Nuclear Receptors, RXR and the Big Bang shows how intertwined the thyroid and steroid hormones are with vitamins, amino acid, carbohydrate, fatty acid, glucose, and xenobiotic metabolism just via RXR alone. Many of my symptoms seem to read like a road map of neural crest cell (NCC) derivatives (See Wiki Neural Crest, and scroll down to “Cell Lineages” [Cranial, Trunk, Vagal, Cardiac] and “Neural Crest Derivatives” [Mesectoderm, Endocrine, Peripheral Nerves, Melanocytes]. Note how NCCD’s make up the connective tissue of the head and neck glands [thyroid, pituitary, thymus, salivary, lacrimal], tendons of ocular and masticatory muscles, dental related cells, peripheral nerves including of the head and neck, the catecholamine releasing chromaffin cells of the adrenal medulla, calcium regulating parafollicular cells of the thyroid, oxygen/carbon dioxide and pH sensing glomus cells in the carotid and aortic bodies, etc. Also note that paraganglioma-like symptoms are high on my differential list for my “flares”, either as a pathological process or as an appropriate compensatory response for problems elsewhere [scroll to “Horrible Flare“; here I consider mitochondrial succinate and aKG area] ). In Topoisomerases – The Obvious Targets, I ask the question, what underlying factors do these NCC’s continue to have in common in the adult despite being differentiated? RXR genes (1) may be one such example. Interestingly, one of the many adverse effects of Isotretinoin, which has a close molecular resemblance to retinoic acid, includes Achilles tendon pain and rupture (do a search on Accutane and tendonitis or tendon pain for descriptions by patients; also see transthyretin (TTR) down on this page under “Carrier Proteins”). This could be due to some as of yet unknown connection (1), or possibly due to the RXR/VDR connection, affecting Vitamin D and Calcium homeostasis (see below). Mefloquine, a quinoline, has a similar CNS adverse effect profile to the quinlones; an interesting hypothesis relating a retinoid (Vitamin A) toxicity to quinoline toxicity is presented here (Please note that in this paper, the word quinolone is a typo, and they should all be replaced with the word quinoline; I confirmed this with the author.) An interesting study I would love to see repeated with quinolones is this one here. For more Aldehyde/Thyroid related references, see here, scroll down to “Aldehyde Dehydrogenases”.
Selenoenzymes/Selenoproteins: These include the five glutathione peroxidases, the iodothyronine deiodinases, and thioredoxin reductases, as well as additional selenoproteins. The obvious connections here for my purposes are the relationships of Se to thyroid hormone and de-iodination and glutathione. Se is also heavily involved in cell homeostasis, in that selenoproteins act as a “gatekeeper” for cells. FQ’s are known to bind divalent and trivalent cations; I question whether the same could occur with Se++. Intravenous glutathione infusions are one of the treatments that some flox victims try, with varying rates of success.
Peroxidases/Haloperoxidases: The obvious connection here for my purposes are the haloperoxidases, of which TPO is one. I very obviously had an iodine organification problem, most likely not only within the thyroid gland, but within other cells of my body as well. MPO (myeloperoxidase), LPO (lactoperoxidase) , EPO (eosinophil peroxidase), IPO (intestinal peroxidase) are haloperoxidases. These peroxidases are also heme dependent as well. Glutathione peroxidases are also in this peroxidase category as well as being selenoenzymes. Porphyrias should also be considered in the differential diagnoses, and tested for in flox victims experiencing an acute reaction or during “flares”.
SLC5A (Solute Carrier Family 5A): These include transporters for glucose, galactose, iodide, choline (carries choline into ACh synthesizing neurons), some B vitamins, myoinositol, and more. FQ adverse effects include dysglycemias, thyroid hormone/iodine metabolism disruption, and neuromuscular disruption. Of course, there are any number of other SLC’s that could be affected as well; a quick look at the list could easily expand the possibilities considerably. I’m focusing on 5A here because of the NIS/SMVT transporters and their possible significance in my particular situation. However, I also developed glucose issues, B vitamin sensitivities, and increasingly suspected ACh-related issues in me as well over time.
Channelopathies: I strongly suspect one or more channelopathies playing a role in my reaction, and in flox reactions in general. Sodium, potassium, and calcium shifts underlie most, if not all, of the biochemical reactions occurring in our cells, with other ions filling in the rest. Ion channels are pore-forming proteins that provide pathways for the controlled movement of ions into or out of cells, as well as many cellular organelles (such as mitochondria). Ion channels coordinate electrical signals in most tissues and are thus involved in every heartbeat, every movement, and every thought and perception (1,2). Note the word “controlled”. If this control is disrupted, homeostasis can be severely disrupted. I discuss how this disruption felt to me in “It Felt Like a Homeostasis Problem”. The extreme sensitivity to everything: changes in movement, temperature, light, sound, pressure, exercise, various foods or just the act of eating, hormones, even emotions (endogenous hormonal and neurotransmitter surges during laughing or crying) can act as triggers in channelopathies. Scroll through the Wiki list of channelopathies to see the variety of (familiar) symptoms, from mild to extreme, that can occur as a result. Most channelopathies are considered congenital due to gene mutations. Acquired channelopathies are often considered autoimmune in nature. When it comes to the FQ’s, I wonder if acquired “de novo” mutations or epigenetic modifications might occur as a result of the FQ. Polymorphisms in ion channel genes, which might not normally affect a person, might also be “unmasked” or contribute to ADR’s in carriers of these gene variants. In my particular flox case, I think that any of these is a possibility.
Divalent/Trivalent Cations: FQ’s form metal complexes due to their capacity to bind metal ions such as divalent and trivalent cations (Ca, Mg, Mn, Ni, Cu, Zn, Fe, Co, Al, etc.). A major ongoing hypothesis of FQ Toxicity is that FQ’s are complexing with these cations, leading to a systemic deficit and/or loss of homeostasis of important minerals and trace minerals necessary for function (and/or, people with existing low Ca/Mg/mineral status are more susceptible to FQT). Magnesium deficit and homeostasis disruption has been a major ongoing hypothesis of FQT, with numerous studies substantiating this. Low Ca and Mg status, along with high PTH levels, can result in recognizable FQT neurological symptoms, as well as tendon ruptures (see “The Parathyroid Glands and Calcium Homeostasis” below). Ca and Mg homeostasis are extremely important for regulating acetylcholine function as well, which also could easily participate in FQT neurological symptoms (here and here). Magnesium is extremely important, known to be utilized in over 300 enzymatic reactions in the body. Virtually all enzymes required for DNA synthesis and repair require Mg, and this includes the topoisomerases that the FQ’s target. This, more than anything else, can easily explain why the damage can be so severe, and ultimately, permanent, for some FQT victims. Tyrosine kinases, extremely important in cell signaling processes, also require divalent cations, with Mg being a major one (see “The Magnesium Connection” in TKI’s: An Existing Example of Chemotherapeutic Drug Induced Acute, Delayed, and Permanent Thyroid Problems. Can FQ’s Act as TKI’s?). Although Mg and Ca have been the main focus of suspected FQT, I suspect that many minerals and trace minerals may potentially be affected. Manganese in particular can sometimes be used as effectively or more so in some enzymatic reactions that utilize magnesium, and manganese toxicity can result in Parkinsonion-like tremors. Iron is extremely important in heme based enzymes, which happen to include TPO, MPO, EPO, LPO, etc. Copper and zinc are equally important trace elements responsible for the function of many cellular enzymes and proteins. For my purposes here, I question whether Selenium and Iodine should also be on the list. Iodine can assume positive oxidation states. As to how common these states are in the body, or how likely FQ’s are to affect iodine directly, I don’t know. However, my entire website is about how I believe Cipro affected my TH and Iodine metabolism and homeostasis, with iodine itself being a major player. Inhibition of tyrosine kinases and phosphatases also appears to be a potential mechanism of NIS regulation, so that could be another possibility. Homeostasis of minerals and trace minerals could be disrupted by any number of mechanisms; for example, if receptors or transporters for these (ex: metallothioneins) are damaged directly in somatic cells or mitochondria, cellular or mitochondrial membranes are damaged, or genomic damage/mutations for these occurs. I’ve even questioned whether or not allergenic or autoimmune responses could develop to metal cofactors, alone or in specific proteins. Nickel allergies exist; what the specific mechanism for that is, I’m not sure, but could the same occur with Mg, for example? I would imagine DNA strand breaks with FQ-Mg-tyrosine residues “waving in the breeze” on the ends of those breaks, would be a strong signal or target for the “clean up crew” — inflammatory and immune cells. This FQ-Mg-tyrosine foreign wad could possibly become highly antigenic when cell or mitochondrial death occurs, perhaps resulting in specific Mg-tyrosine residues eventually becoming antigenic targets as well. I don’t know — but it’s a thought. Many drugs can complex with metal ions; for example, the antibiotic doxycycline also chelates Ca and Mg, which could also result in a systemic deficit. Yet, it does not cause the extreme tendon pain or the same “syndrome” that the FQ’s do. This is one reason why I feel the “Mg-Tyrosine” combination, important in so many replication, signaling, and receptor processes, may be a target, and not just the loss of Ca or Mg itself. A very plausible mechanism relating Calcium disruption and FQ-V-ATPase interaction, accounting for many FQT/FQAD symptoms including tendon ruptures, can be seen here and here (scroll down about 60% of the page to “V-ATPase”).
“The Tyrosine Connection”: During my research, it often seemed like “all roads lead to tyrosine”. It has a unique role in cell signaling processes due to its phenol functionality. Obvious connections here are its role in TH synthesis and metabolism, as a precursor to neurotransmitters (dopamine and catecholamines such as norepinephrine and epinephrine), and as precursors to CoEnzymeQ synthesis and melanin pigment synthesis. I include Tyramine (and its relationship to MAO) here as well. Tyrosine also appears to play a specialized role in higher order structure and function of the collagen triple helix via telopeptides. Tyrosine transporters also play a role in metal ion homeostasis and toxicity. Membrane proteins, which are the targets of over 50% of modern pharmaceutical drugs, show an astounding accumulation of tyrosine and tryptophan residues, which appear to perform vital anti-oxidant functions and protect cells from oxidative destruction, as well as enhance membrane stabilization. Tyrosine, tyrosyl residues, and phosphotyrosyl bonds are important structural and functional moieties for innumerable processes throughout the body. Because of the aromatic nature of FQ’s and the symptomatology which often occurs in FQ victims, I question whether FQ’s might be acting as a structural analog or inhibitor of receptors, transporters, or in other binding processes involving aromatic amino acids. The 4-Quinolone Quorum Sensing molecules that bacteria produce are described as “hormone-like” and production is highly affected by the aromatic amino acids in the nutritional environment, as discussed in this most interesting paper here. In my opinion, this further strengthens the link between aromatic AA’s such as tyrosine and FQ’s. FQ’s bind close to a functionally important and crucial tyrosine residue in the enzymes they target, and I question whether they are targeting additional enzymes and receptors with similar functionally important tyrosine residues, especially where Mg++ is a cofactor. Anything that affects tyrosine metabolism could potentially affect any structural, receptor, enzymatic, cell signaling or signal transduction reaction tyrosine is crucial for. See References 8 and Additional 8A. Recent 2015 paper on role of both Tyrosine and Tryptophan in protection against oxidative damage here. Quinone cofactors derived from aromatics are involved in a variety of biological reactions; formation or functionality of these quinoenzymes ( 1, 2, 3 ) may be affected by FQ’s. Quinones, hydroquinones, semiquinones and their metabolites are naturally occurring compounds that serve as substrates and products, including intermediates in many pathways of gene regulation, enzyme protein induction, feedback control, and waste product elimination. They play a pivotal role in energy metabolism and many other key processes, including chemotherapy where redox cycling drugs are utilized ( 1 ).
Tryptophan Metabolism: If all roads lead to tyrosine, then tryptophan (Trp), another important aromatic amino acid, would be a very close second for me. As with tyrosine, because of the aromatic nature of FQ’s and the symptomatology which often occurs in FQ victims, I question whether FQ’s might be acting as a structural analog or inhibitor of enzymes, receptors, transporters, or in other binding processes involving aromatic amino acids, which in this case, would be tryptophan. According to one author, “Tryptophan can be replaced by other aromatic residues, but it is unique in chemistry and size, meaning often that replacement by anything could be disastrous.” Somehow I get the feeling this disaster occurred in me during the acute phase of my reaction, and continues today with my chronic reaction. Symptomatic clues that led me to question Trp metabolism problems as playing a role in my floxing were the “serotonin syndrome – like” symptoms I experienced post flox, similar symptoms I had experienced pre-flox many years ago with only a few days trial of Prozac and St. John’s Wort, and symptoms experienced post flox with trials of tryptophan and 5-HTP supplements. What is surprising to me, in particular, is how much it felt like serotonin affected my eye pain and vision problems (along with other symptoms of “too much” serotonin). One major branch of tryptophan metabolism is that of serotonin production, which most people know has a broad impact as a neurotransmitter and neuromodulator and has been implicated in numerous psychiatric conditions and psychological processes. Lesser well known to the general public is an equally important second major branch of tryptophan metabolism for the synthesis of a number of metabolites, including kynurenic acid and quinolinic acid, both important in their relationship to NMDA receptors, glutamate, and influencing important neurophysiological and neuropathological activity and processes. Through these same pathways, tryptophan also plays a major role in melatonin and niacin production as well. Quinolinic acid in particular has a potent neurotoxic effect, acting as an NMDA receptor agonist (and several references have implicated NMDA receptors in FQ-induced neurological symptoms as well, see References 11) and may play a role in suicidal behavior (1). Furthermore, quinolinic acid, which normally doesn’t cross the blood brain barrier, can do so under inflammatory conditions, which can then contribute to further degradation of the blood brain barrier, which then results in even higher concentrations of quinolinic acid in the brain, resulting in a damaging cycle. I often wondered if tryptophan metabolism problems, with quinolinic acid buildup and NMDA receptor agonism, were contributing to some of my severe CNS symptoms. I of course have no objective proof of this, but I often *felt* like rapid or sudden shifts between quinolinic acid and serotonin could be occurring, ie, loss of homeostasis between these two pathways. Importantly, a number of intermediate and additional products of the tryptophan metabolism pathway are necessary for immunosuppressive functions and disease tolerance. The kynurenine pathway is a key regulator of both the innate and adaptive immunity through its involvement in cancer, autoimmunity, and infection. Tryptophan is mainly catabolized through the enzymatic activity of the dioxygenase enzymes TDO and IDO (under physiological conditions TDO is the main enzyme degrading Trp; in the context of infection, IDO becomes induced and is the main degradatory enzyme). Note that both TDO and IDO may very well be susceptible to inhibition by FQ’s, as described below under 2KG: Dioxygenase enzymes. IDO is involved with inflammation and the control of acute and chronic infections, and metabolic immune regulation of IDO involves the protection of the host from over reactive immune responses via the induction of systemic immune tolerance. Tryptophan breakdown is necessary for maintaining aspects of immune tolerance. I often wondered whether the immune/autoimmune homeostasis problems I experienced were in part due to TDO/IDO problems, perhaps due to epigenetic silencing or enhancement by the FQ. IDO also interacts with a receptor called AhR (involved with regulation of biological responses to aromatic (aryl) hydrocarbons) that induces detoxifying enzymes (xeno-biotic metabolizing P450 enzymes) and can be involved with global changes in gene expression leading to adverse changes in cellular processes and function. AhR also creates a positive feedback loop with IDO and Kynurenine to maintain a state of immune tolerance between commensal microbiota and the host. I wonder if perhaps these mechanisms might potentially play a role in gut autoimmune conditions such as Crohn’s disease or “leaky gut”. The distinguishing structural characteristic of Trp is that it contains an indole functional group. Tryptophan residues are important in many receptor binding pockets which utilize aromatics, such as the nicotinic and muscarinic receptors, as well as the cation-selective ligand gated ion channel receptors which include 5-HT3, nACh, GABA and glycine receptors. Additionally, membrane proteins, which are the targets of over 50% of modern pharmaceutical drugs, show an astounding accumulation of tyrosine and tryptophan residues, which appear to perform vital anti-oxidant functions and protect cells from oxidative destruction, as well as enhance membrane stabilization. Note how this paper states that “the quinolones family of drugs seem to link three different biological activities: antibacterial, anticancer, and the antiviral profiles.” The same is true of tryptophan metabolism, and abnormalities with Trp metabolism have been implicated in a wide variety of disorders, including neurological, neuropsychiatric, immunity and autoimmunity, Autism, and more. I wonder if Trp metabolism issues might be one underlying mechanism to consider in Post Viral, Post Bacterial, and Post FQ Syndromes. The gut microbiome can also play a role in providing Trp and even serotonin if other avenues fail, but of course during antibiotic treatment, much of the “good gut bacteria” are at least temporarily wiped out, if not also permanently affected by treatment, further blocking another source of Trp for use. If Trp metabolizing enzymes AND associated gut bacteria are wiped out, effectively wiping out serotonin, this could contribute to the severe crashes and crying jags and depression from hell described by FQT/FQAD victims during the acute phase of the reaction. The aromatic FQ’s potential structural and functional relationship to tryptophan and it’s metabolites may contribute a role in many of the symptoms in FQT/FQAD. As always, for people with healthy and normally functioning tryptophan-related metabolism and homeostasis capabilities (all enzymes, receptors, transporters, gut bacteria, etc. functional when it comes to tryptophan), I suspect that a temporary increase, decrease or even wipeout of tryptophan and/or metabolites or enzymes involved in metabolism might not cause a problem. For people who don’t react at all to these drugs, they probably never even feel the fluctuations, as compensatory mechanisms exist to help them automatically rapidly adjust to a change in tryptophan or metabolizing enzyme availability. But I would suspect that anyone with any underlying genetic or epigenetic predisposition in enzyme availability, a critical tryptophan residue abnormality in a receptor or enzyme, or possibly harboring a subclinical, latent, or silent tryptophan metabolism and homeostasis issue, might be “pushed over the edge” into full blown flox symptoms. If I had the opportunity, I would love to test Trp/serotonin-related genomics, epigenomics, and enzyme function in me, as I suspect this played a role in my acute reaction, and may continue to play a role in my permanent reaction today. There’s a lot to tie in together in this paragraph; for interesting and relevant Trp references see References 13.
The Parathyroid Glands and Calcium Homeostasis: The major function of the parathyroid glands, which are basically located on the thyroid gland, is to maintain the body’s calcium and phosphate levels within a very narrow range, for proper neuromuscular function. Hypocalcemia can cause a range of neuromuscular issues, from mild tingling and numbness of any part of the body, but especially of the extremities and face/head, to more severe “electric shock” like pains, muscle twitches and fasciculations, to outright full body, often conscious seizures or tetany (which some flox victims appear to experience). FQ’s are known to bind divalent and trivalent cations, and disrupt intracellular and mitochondrial calcium homeostasis; this could potentially result in an acute transient or longer term chronic systemic calcium deficit, which would in turn result in increased parathormone production. Symptoms of hypocalcemia are highly exacerbated and more apt to occur with hypomagnesemia as well, and FQ chelation or binding of Mg has long been an ongoing hypothesis. Interestingly enough, numerous studies exist showing the association of spontaneous tendon ruptures with increased parathormone and decreased calcium – conditions usually associated with chronic renal failure. The FDA has stated that FQ’s are contraindicated in chronic renal failure patients due to increased risk of tendon ruptures, presumably due to this parathormone and calcium homeostasis disruption. Hypercalcemia is no better, with symptoms of fatigue, muscle weakness, constipation, drowsiness, confusion, hallucinations, stupor and coma, vertigo, dizziness, eye pain, gastro pains, joint, muscle and tendon problems, and more. Hypercalcemia is most often due to a parathyroid adenoma. It’s not often that a chronically disabling condition full of suffering has a surgical cure, but this is one of those times. I think every flox victim owes it to themselves to be checking and monitoring for this because there actually is something that can help in this case (See Thyroid and Parathyroid Related Testing and Testing On Your Own — When the Docs Refuse). A connection here for my purposes is that I have an autoimmune Destructive Thyroiditis, which could conceivably affect or destroy my parathyroid glands as well, thereby compromising calcium and phosphorus homeostasis in me. I question if primary adenomas could be accounting for or contributing to some of the “flaring” that I experience, with adenoma formation being a compensatory response to original tissue destruction on both the thyroid gland and parathyroid glands. Of course, calcium homeostasis disruption could be occurring at a cellular and mitochondrial level as well. There is an entire neuroendocrine system within the thyroid gland itself, with all kinds of functional significance, most of which is probably unknown. If the thyroid tissue is destroyed, the thyroid gland removed, or perhaps simply with suppression of the thyroid axis due to medication, this could affect the functions of this thyroid-neuroendocrine system. This may be why some people do much better with the natural desiccated thyroid than with simple replacement of T4 and T3. Getting rid of the thyroid gland, either via disease, surgical removal, or suppressive medication most likely destroys much more than just “simple thyroid hormone production”. A very plausible mechanism relating Calcium disruption and FQ-V-ATPase interaction, accounting for many FQT/FQAD symptoms including tendon ruptures, can be seen here and here (scroll down about 60% of the page to “V-ATPase”).
Cytochrome P450’s: It is known there is a huge variation in cytotoxic drug clearance between individuals due to genetic and environmental factors. For example, the major oxidizing enzymes for many cytotoxic drugs can vary by as much as 50 fold. On top of this, many drugs or disease states are known to inhibit or induce CYP activity, further adding to this variation. CYP P450’s are also hemoproteins (think Porphyria again). Cytochrome P450 genomic testing will become more and more common over time; here is one example of what is currently available. A more detailed discussion using CYP1A2 as an example is provided here.
Purine Metabolism and Salvage Pathways: Structurally, FQs as a class resemble purine derivatives, which include not only adenine, guanine, isoguanine, xanthine, hypoxanthine, caffeine, theobromine and uric acid, but ATP, GTP, cAMP, cGMP, NAD, FAD, NADH, coenzyme A and more. Disorders of purine metabolism are being studied for many conditions, and have been implicated in Autism and Alzheimer’s, and most recently, in CFS/ME. Although purines are essential in all cells of the body, the clinical manifestations of these disorders often suggest the nervous system to be more seriously affected than other organs, both peripherally and centrally. Several pathogens are known to rely on their mammalian host for salvage of purine bases for their survival as well, such as B. burgdorferi (Lyme’s disease), Plasmodium spp (malaria), and H. pylori (gastritis/peptic ulcers). Purine metabolism, salvaging, and signaling dysfunction may be a common denominator to consider in FQT/FQAD and these disorders, as well as other “chronic invisible illnesses”. One of the reasons I think the “FQ-CYP1A2-Methylxanthines” connection is so important, is because it opens the door to looking at purine metabolism and salvage pathways (see extensive write up on this under Cytochrome section “CYP1A2/3A4” in Part 2 link). There are a lot of enzymes involved in purine metabolism, but one of the most studied and utilized in studies is xanthine oxidase (XO), and I wouldn’t be surprised if FQs are XO inhibitors, as suggested in this study here. Perhaps permanent XO/XDH disruption, or in other enzymes involved in purine metabolism and salvage pathways, is occurring in those of us with FQT/FQAD. Although any number of possibilities exist, I wonder if my now severe intolerance to milk and dairy products might be due to some problem with XO, including possible autoimmunity to it. An interesting example of how antibodies can target purinergic ATP receptors, and essentially mimic the effects of ATP (as well as acetylcholine), is described in this recent study here. Many purine, tyrosine, and tryptophan based alkaloids exhibit anti-cancer activities. Using the “FQ-CYP1A2-Methylxanthines” connection as a starting point, I think a tremendous amount could probably be learned about purine metabolism and salvage pathway disorders via FQs and FQT/FQAD.
Topoisomerases: As the target enzymes of the FQ’s (1, 2), these are an obvious first place to look for problems. Looking at both the nuclear and mitochondrial genomics and epigenomics of all known human topoisomerase enzymes, as well as all other enzymes involved in DNA replication and repair (many of these utilize tyrosine in the active site, Mg as a cofactor, and ATP), should be done for the FQ-affected population to look for potential mutations. If suspect differences are found, comparisons should then be done with homologous bacterial topoisomerase enzymes, to see if there are any mutations in common (ie, compare resistant and susceptible bacterial DNA with “resistant” and “susceptible” human DNA). If differences are found in the FQ-affected population, comparisons should then also be done with parental nuclear and/or mitochondrial DNA, which might help suggest a predisposition versus FQ’s acting as an environmental human mutagen. Although we’re in the early stages of the genomic revolution, this is something that can be done NOW, even if we have limited information on which genes are responsible for which enzymes. Mitochondrial enzymes, transporters, etc., may be natural targets of FQ’s; these are similar suggestions as I made here in “Mitochondrial Damage and Depletion” to test for Mitochondrial Disease. If anything of significance is found in the FQ-affected population, I hope similar testing will then be done on others diagnosed with other “Post Viral, Post Bacterial, and Post Chemo” conditions for the reasons I gave in those writings. Problems with DNA replication and repair enzymes most certainly could cause the long term and permanent effects seen with the FQ’s. I would imagine proteins with continual extreme rapid turnover would be affected first (which might include the topoisomerases). I also suspect cells with secretory functions, such as in the endocrine and neuroendocrine system, might be hard hit. I discuss this more in Topoisomerases – The Obvious Targets.
2-KG Dioxygenases, P4H: I am basing this on two papers: The first, a recent Mayo Clinic 2015 study entitled Non-antibiotic effects of fluoroquinolones in mammalian cells, describes FQ inhibition of enzymes called 2-KG dioxygenases. This was only an in vitro study, but it suggests a mechanism not only for FQ-Induced Tendon and Collagen and Renal damage, but may account for the long-term or permanence of these reactions via epigenetic changes. Additionally, I find the suggestion that FQ’s may abolish a protein called “HIF-1 alpha” concerning for the majority of the population who take these drugs but don’t have cancer. The second paper entitled Prolyl 4-hydroxylase describes the importance and relationship of P4H in collagens and elastin formation in tendons and other connective tissues, in neuromuscular transmission (AChE , 1, 2, 3, 4, 5), in the innate immune system and potential autoimmunity (C1q and collectins/lectins), in relationship to thyroid metabolism (p55 thyroid hormone binding protein 1, 2, 3, 4), in protein folding and ER retention (PDI), in glutathione metabolism and insulin degredation (GIT), in gene silencing (Ago2, 1), in binding domains of steroid receptors, and more. As of this writing, I tend to lean quite a bit towards the inhibition of P4H’s as a viable hypothesis to explain many of the potential symptoms and severe syndrome of adverse effects that can develop in those of us with FQT/FQAD. This includes the hypersensitivity / “autoimmunity” which appears to affect some of us (either via collectins/lectins or protein misfolding), and also provides a mechanism to account for the long term and permanence of some of these reactions. Dysfunction of the multifunctional beta subunit of P4H or cellular ER expands the potential problems considerably. As an example, many of my symptoms seem to involve secretory epithelial cells, or cells that produce large amounts of and/or cellular products at a rapid rate, with well developed ER/Golgi or secretory vesicles, for example (ER Stress). This would include neurotransmitter, neuroendocrine, and endocrine and exocrine gland cells, for example, but would also include a wide variety of other proteins which need to continually and/or rapidly be replaced, such as some collagens (via P4H) and keratins. This would also include proteins which are drastically depleted and need to be replaced due to the FQ promiscuously binding to them as well. Since many people take an FQ without apparent problems, as usual, I would suspect a genetic or epigenetic pre-disposition to be occurring somewhere in the chain of events involving P4H’s for those of us affected. See Thyroid Damage Due to Collagen/Connective Tissue Damage for an example of how a connective tissue or collagen disorder might contribute to or cause an endocrine disorder, and more on this research. Of interesting note is that one of the more popular pages on this website is the Phantosmia page. That “disulfide bond/cysteine” smell from TH, Iodine, and other substances suggests something is going on in that area resulting in excreted substances then acting as a sulfur based ligand on the olfactory epithelium. I wonder if that “something” has to do with protein misfolding or sulfur bond breakage occurring either within the olfactory epithelium or the respiratory epithelium in the paranasal sinuses due to PDI problems. A large part of my facial/CNS symptoms has to do with severe pain, “tightness”, burning, dryness, and what feels like “fluid homeostasis” problems in the paranasal sinus epithelial cell lining, with the focal point feeling like it’s right on that olfactory bulb area. In addition to TH/Iodine, two supplements that severely exacerbated these symptoms, including the phantosmia, for me included selenium and alpha keto-glutarate. Overall, depletion or damage of PH’s, or the beta subunit of P4H’s, could have some very widespread effects, with epigenetic changes contributing to the long term and/or permanence of some reactions. Note also that dioxygenase binding by FQ’s may include more than the P4H and demethylases studied in this first paper. Coming from a symptoms approach, and for additional reasons, I also would put TDO/IDO in tryptophan metabolism, and HGD in tyrosine metabolism on the list (Alkaptonuria can also result in spontaneous tendon ruptures), as well as others. Also, regarding iron, I don’t know if I was ever tested for iron levels pre-flox (although I have never been anemic ). I’ve been monitoring iron and ferritin regularly since 16 months post flox, and my levels have always been good. However, I had been a vegetarian for about 20 years prior to being floxed, so I suppose there’s the potential for “low iron” possibly playing a role in my floxing. I would imagine if someone is also naturally low on some of these iron dependent dioxygenase enzymes due to heterozygosity or existing mutations, this, in combination with low iron status and FQ binding, might increase the risk of FQ ADR’s occurring. Additional discussions on this topic can be found here, under “HIF1a” and “Dioxygenases”.
Sulfation: I described here how It Felt Like a Homeostasis Problem, and how “decompensation” can occur quite easily, with everything from foods, supplements, drugs, exercise, and other environmental triggers. Sulfation issues could play a role in this. Per Wiki, here and here: “Sulfation is involved in a variety of biological processes, including detoxification, hormone regulation, molecular recognition, cell signaling, and viral entry into cells. It is among the reactions in phase II drug metabolism, often times effective in rendering a xenobiotic less active from a pharmacological and toxicological standpoint, but sometimes playing a role in the activation of xenobiotics (e.g. aromatic amines, methyl-substituted polycyclic aromatic hydrocarbons)”. Tyrosine sulfation in particular is emerging in importance, with suggested roles in many secretory and membrane proteins of many different types and classes. From my own experiences and observations of others, FQT/FQAD may be targeting some process(es) involved with secretory proteins, and this could include the enzymes necessary for tyrosine sulfation. Known tyrosine sulfated proteins include TSH and thyroglobulin, among a host of others, and studies indicate that tyrosine sulfation of the FSH, LH, and TSH receptors is required for optimal binding of their ligands. A tyrosine sulfation enzyme, TPST-2, appears to be necessary for normal thyroid gland function, and salivary gland secretion, hypothyroidism, pulmonary function, and tyrosine sulfation issues appear to be linked. In my case, I experienced dry burning eyes, mouth, and lungs as part of my acute and more chronic long term reaction. In “Phantosmia: That Chemical/Smoke Smell” I describe a potentially sulfur based odor occurred when I was highly symptomatic. This could have been due to sulfation issues with secretory cells within the sinus cavities, olfactory bulb, lacrimal glands, pituitary gland, and hypothalamus. From an autoimmune or hypersensitivity perspective, sulfa drugs (antibiotics) certainly are an issue for some people, and foods with higher sulfur based content can be problematic for some people as well. Additional references on sulfation and tyrosine sulfation: 1, 2, 3, 4
Adenosine and Adrenergic receptors: Adenosine plays important roles in biochemical processes, such as energy transfer (ATP/ADP), signal transduction as cAMP, regulation of blood flow, and is also a neuromodulator. Adenosine receptors are involved in processes such a regulating inflammation and immune responses, and release of neurotransmitters such as dopamine and glutamate; they are also targets of the xanthines/methylxanthines. Adrenergic receptors are the targets of catecholamines, primarily norepinephrine and epinephrine. Effects of both are broad based and systemic; both are a class of G-protein receptors. An interesting paper relating adenosine, sleep issues, and the olfactory bulb here: 1 (the olfactory bulb area felt highly symptomatic to me, see Phantosmia webpage). Adenosine, as a purine nucleotide, would also be an important consideration for study within the “purine metabolism and salvage pathways” discussed above on this page.
G Proteins /GPCRs/7TMRs: As with everything else, I arrived at GPCR’s from a symptoms approach alone, along with the feeling that this was some kind of receptor problem in me. There’s an awful lot to look at in this area (there are over 800 GPCRs alone), so narrowing something down won’t be easy. The only good news I suppose is that this is a very active topic for research by Pharma, because it turns out an awful lot of drugs happen to target these proteins. I strongly suspect FQs are one of them. Although there’s no direct research on this yet, the fact that so much research is occurring with other (non-FQ) drugs means an increasing amount of knowledge and information about GPCRs and their related proteins in general will be occurring fast. Because I have FQ-Induced ME/CFS, I always tried to keep in mind potential common mechanisms of pathogens (viral, bacterial, fungal) and FQ mechanisms. I suspect FQs compete for the same proteins and pathway(s) some viruses do; this may be part of their anti-viral mechanisms (see next two pages, Part 1 and Part2). Multiple triggers cause a similar constellation of symptoms, so wherever the problem is, it seems to me it must be common to either the various receptors or probably more likely just downstream of them. I think G-proteins and their receptors should be very high on the list of unintentional targets of FQs, as well as all the proteins immediately involved (regulatory proteins); also include phosphodiesterases. Furthermore, I suspect that at least one mechanism that FQs and viruses/pathogens will have in common in this area will be “phosphorylation events” ( 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18). I often felt like my symptoms reflected a sensitization/desensitization mechanism (see It Felt Like A Homeostasis Problem). I also am in that subgroup of people who feel somewhat better when I’m starting to get a cold or even if I try to exercise just a bit — just enough to increase “inflammatory cytokines” or cortisol? — in a controlled amount (ie, can’t overdo it, or it becomes “too much” and I crash) which is difficult because these reactions can be very “on”/”off”. Once the cold is over, I feel worse again in terms of my FQT/ME/CFS symptoms. I often feel as though I’m not constitutively expressing some important cytokines at a functional basal level, but I can increase them with a stimulus (ie, virus, foods I’m sensitive to, exercise). (Also, for what it’s worth, my serum measured TNF alpha is plastered at the very bottom of the clinical range, can’t really get any lower). It’s estimated that 60% of all the pharmaceuticals used, whether older drugs or the newer ones being developed now, interact in some way with GPCR’s. This doesn’t even include all the drugs we don’t know of that are probably acting at these receptors, which in my opinion, probably include FQs. Here is a nice picture of the Class A Rhodopsin-like gene family hierarchy map. Just a few of the major receptors in this class include adrenergic, dopamine, histamine, 5-HT, mAChR’s, chemokine, P2Y, olfactory, and of course, Rhodopsin receptors. Notice the correlation of these receptors with symptoms of FQT/FQAD and ME/CFS. Click on “family” links for list of specific genes to that family. Additional families include Secretin (glucagon, PTH, calcitonin receptors), Glutamate (metabotropic glutamate and GABA B receptors), and others. See the August 2017 ME/CFS Symposium, for Neil McGregor’s very interesting talk starting at 2:05 on his findings of genetic anomalies in GPCR, RNA helicase, and Langerin related proteins in ME/CFS patients. He included non-coding regions in his genetic search, which I think is important. He ends his talk with cautious optimism about his results so far. My guess is, his findings will be significant.
Epigenetic modifications: This could be occurring as a direct result of damage by the FQ’s, or, as in compensatory responses to damage done elsewhere. For example, my post flox body and cells seemed to “preferentially” utilize iodine over thyroid hormones, or in addition to T3. I question whether this “alternative metabolism of iodine” was “switched on” (or another “switched off”) as a drastic compensatory response to a dramatic and immediate binding up of TH during the acute phase of my reaction, and an inability to utilize thyroid hormone or metabolize it normally chronically after that.
Small non-coding RNAs: Small non-coding RNAs comprise several classes and sizes (miRNA’s, siRNA’s, piRNA’s, etc.), but all share a unifying function in cellular physiology: epigenetic regulation of gene expression. I’m in the camp that happens to believe the 98% of non-coding DNA will eventually prove to be highly significant, for example, for regulatory purposes or perhaps as ancestral “backup genes” in case of catastrophic failures (mutations) of protein coding genes (the latter is my own hypothesis). It’s already known that some noncoding DNA is transcribed into functional non-coding RNA molecules, such as miRNA. The recent discovery of stable and reproducible miRNA in plasma has raised the possibility that circulating miRNAs may serve as novel diagnostic markers, for everything from cancer to autoimmunity to infectious diseases. Consequently, the study of miRNA is a hot topic right now. Not to be left out, a number of FQ’s have been shown to enhance the effects of miRNA’s, and as a result, are being studied for yet another mechanism of action for their “anti-cancer” chemotherapeutic effects (see link below for references). I hope that miRNA microarray expression profiling and validation will also be done within the floxed population, in the hopes of finding a unique biomarker profile for us. MicroRNA might be another common denominator to consider in Post-Viral, Post-Bacterial, Post-Chemo, and Post-FQ syndromes, but with the possibility that distinguishing unique profiles would be found for each of these populations. I discuss miRNA’s and provide some reference links in Thyroid Damage Due to Collagen/Connective Tissue Damage (scroll down to “Research”). Additional discussion on this topic can be found here, under “MicroRNA”.
Mast Cell Activation/IgG4/Eosinophilic Disorders: This is something that I started seriously considering around Year 4 or so, in particular for these “flares” I experience. The progressive symptoms I’ve been experiencing seem to match many of the descriptions I’ve been reading about, and certainly these responses are very “on/off”, immediate, and dramatic. Although they can occur immediately after eating, they also seem to occur randomly. I do not believe that iodine itself is toxic. However, I do suspect that iodinated proteins, and any intermediate metabolites with reactive iodine, could be targets. This would include, for example, the haloperoxidases and their intermediates, with TPO being the obvious target in me. After that, I would suspect glutamate, glutamine, and glutamic acid residues as targets, proline-rich epitopes or motifs, or possibly aromatic amino acids, in particular, tryptophan. Of course, any number of exogenous or endogenous proteins could be a target of this. High on the list are lectins, found in many or most foods to some extent. Mast Cell flaring could be occurring in tandem with other instigating factors in my flares, or, could account for many of my symptoms alone. See “References” section on this website for more information on Mast Cell Activation Syndrome, or see these papers here and here.
Carrier Proteins (Albumin): I described here how It Felt Like a Homeostasis Problem, and how “decompensation” can occur quite easily, with everything from foods, supplements, drugs, exercise, and other environmental triggers. Carrier proteins are another target I considered, and here, I focus on albumin. Human Serum Albumin (HSA) is the major protein both in the plasma and in the interstitium, often functioning as a carrier protein, and significantly involved in maintaining homeostasis of many of its ligands. Despite this, it is a rather “forgotten” protein, when it comes to contributing to potential pathology. Albumin is an important multifunctional protein with extraordinary ligand binding capacity and undergoes conformational transitions with pH changes which are essential for completing its physiological roles. It functions as a transporter molecule for a diverse range of metabolites, organic compounds, fatty acids, nutrients, hormones, metals (Ca, Mg, Zn, Cu, Fe, etc.), Vitamin D and its metabolites, bilirubin, possibly glutathione, and many drugs, including NSAIDS and fluoroquinolones. Albumin binds drugs and ligands, and therefore reduces the serum concentration of these compounds; for example, it acts as a “buffer pool” to stabilize the plasma concentrations of Ca, tryptophan, and hormones, including cortisol, testosterone, and estrogens. Half life of albumin is 19 days, compared with a few days or less for other circulating proteins. Albumins are also allergenic and antigenic, and exhibit a high degree of cross-reactivity due to significant sequence and structure similarity of albumins from different organisms. In my view, the significance of all of the above is that if the function of albumin is somehow damaged, either via genomic/epigenomic mechanisms, post-translational mechanisms, or even allergenicity/antigenicity mechanisms, a major form of homeostasis for the body will be severely disrupted. Food allergies, metabolic and nutrient homeostasis issues, cation/anion homeostasis issues, and sensitivity to most, if not all drugs and chemicals could easily occur with albumin disruption. Alternative pathways exist for many substances; for example, when it comes to hormones, thyroid hormones are mostly carried by TBG and TTR, cortisol by CBG, and sex hormones by SHBG, with albumin acting almost like a reservoir “sink”. This might potentially account for one reason why homeostasis of these hormones is so compromised — but it doesn’t kill us (even though it often feels like we’re dying). The same could be true of all the other substances that albumin transports, for example, accounting for my sensitivity which developed over time to minerals and trace minerals, fatty acids (I cannot tolerate omega’s or many oils anymore), endogenous metabolic substances produced during exercising, and of course drugs, supplements, and chemicals. The half life of albumin also is in keeping with the time frames for acute FQ reactions, similar to what I proposed for thyroid hormones. Serum albumin levels have always been normal in me, but what I am proposing is that the function of albumin is being compromised, not the production of it. Please note that analbuminemia is considered a benign condition, and that people do live with it – how that plays into what I am suggesting, I can’t say, except that perhaps allergenicity and antigenicity issues might play a larger role for flox victims. Or perhaps that for those of us born with functional albumin, compensatory mechanisms may not be in place, at least initially, leading to catastrophic symptoms if the carrier capacity of this protein is suddenly wiped out or damaged. I also question if it’s possible FQ’s could literally “knock off” Ca, Mg, or NSAIDS from albumin binding sites, or prevent Mg, Ca, and NSAIDS from binding to albumin, resulting in any number of effects, such as transient elevations of these substances. This could then trigger a cascade of effects, such as resulting in low or hypo Mg/Ca if FQ’s then bind to free Ca and Mg as well, making it unavailable for use and also low in the serum. FQ’s could easily promote allergenic-like, hypersensitive, and autoimmune responses with albumin as well, certainly as much as any other completely synthetic foreign drug, and probably more so. Studies have shown that FQ’s can affect isolated aromatic amino acids such as tyrosine, that proteins can be considered a major target at the molecular level in the mechanism of action of fluoroquinolones, and tyrosine residues are important for some functions on albumin. Albumin is also important for a multitude of other functions such as osmotic pressure, free radical scavenging, acid-base balance, anti-coagulant effects, and vascular permeability. I’m spending a little extra time on albumin here, because I think it’s often overlooked as contributing to any type of chronic medical condition. I wonder if it’s an obvious target “hiding in plain sight”. In the research world, “everyone knows” that albumin is an important part of drug metabolism and contributes to system homeostasis, and yet it’s rarely considered as a potential agent of any permanent medical problem or symptoms (other than “allergies”), perhaps because analbuminemia exists as a benign condition. And of course, everything I’ve written about could be caused by any number of other mechanisms as well. Still, I throw it out here as a consideration and “on the list” of places to look. Albumin could be researched extensively, but I provide a few references here to start: References 12. Many of the statements I wrote above about functions of albumin were pulled directly from these references. Note that one of the transport proteins of T4 called transthyretin (TTR), also acts as a carrier of retinol (Vitamin A) via retinol binding protein. Numerous genetic variations within the TTR gene are known to correspond to amyloid diseases causing polyneuropathy, cardiomyopathy, and tendon problems.
Fluorine: Fluorine is an obvious culprit for a variety of reasons. Evidence for this exists in that it was used in the treatment of hyperthyroidism in the past, as it shuts down production of thyroid hormones. I have purposely stayed away from covering fluorine in this website here, as it is covered quite extensively throughout the internet. However, I do believe that fluorine may be playing a greater role in all kinds of maladies, including with thyroid hormones. This makes all drugs with fluorine residues suspect. It’s hard not to notice all those fluorines on gas anesthetics such as isoflurane and sevoflurane, Mefloquine (Lariam), the sister drug to the quinolones, and antidepressants such as Prozac, all of which can cause similar severe CNS adverse effects. To me, this implies greater CNS penetration with the addition of fluorine, or possibly, halogenated drugs overall. Approximately 20% of commercialized pharmaceuticals contain fluorine, and depending on which one you get, and for how long, you could be getting a fairly hefty dose of a substance not normally found in great amounts in our body. This alone should be a big red flag for anyone considering taking a fluorinated drug. Something to consider is that nalidixic acid, considered the precursor to the quinolone antibiotics, did not have a fluorine residue but is reported to have exhibited similar adverse effects as the FQ’s. So although I don’t think fluorine alone is responsible for the adverse effects of the FQ’s, it may potentiate the ADR’s. Fluorine is stored in our bones, and one possible mechanism to consider with fluorine release due to FQ use would be similar to Lead Toxicity, discussed here. The internet is filled with information, here are a few links to get you started: 1, 2, 3.
Acetylcholine, Glutamate/GABA, Mitochondrial, Collagen/Connective Tissue, Topoisomerases, and Tyrosine Kinase Inhibitors are discussed separately. A discussion of miRNA is provided here (scroll down to “Research”). The next two pages also review some of these topics, as well as explore new ones, and provide numerous references organized by topic (Part 1 and Part 2).