Review Article: Treatment of The Fluoroquinolone-Associated Disability: The Pathobiochemical Implications

Hindawi
Oxidative Medicine and Cellular Longevity

Volume 2017, Article ID 8023935, 15 pages
https://doi.org/10.1155/2017/8023935
Review Article
Treatment of the Fluoroquinolone-Associated Disability:
The Pathobiochemical Implications
Krzysztof Michalak,1,2 Aleksandra Sobolewska-Włodarczyk,3 Marcin Włodarczyk,3

Justyna Sobolewska,4 Piotr Woźniak,4 and Bogusław Sobolewski4
1
Physics Faculty, Laboratory of Vision Science and Optometry, Adam Mickiewicz University in Poznań, Umultowska Street 85,
61-614 Poznań, Poland
2
Nanobiomedical Center of Poznań, Umultowska Street 85, 61-614 Poznań, Poland
3
Department of Biochemistry, Medical University of Lodz, Mazowiecka Street 6/8, 92-215 Łódź, Poland
4
Outpatient Clinic, Polish Mother’s Memorial Hospital-Research Institute, Rzgowska Street 281/289, Łódź, Poland
Correspondence should be addressed to Aleksandra Sobolewska-Włodarczyk; [email protected]
Received 1 July 2017; Accepted 20 August 2017; Published 25 September 2017
Academic Editor: Jacek Kurzepa
Copyright © 2017 Krzysztof Michalak et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Long-term fluoroquinolone-associated disability (FQAD) after fluoroquinolone (FQ) antibiotic therapy appears in recent years as a
significant medical and social problem, because patients suffer for many years after prescribed antimicrobial FQ treatment from
tiredness, concentration problems, neuropathies, tendinopathies, and other symptoms. The knowledge about the molecular
activity of FQs in the cells remains unclear in many details. The effective treatment of this chronic state remains difficult and
not effective. The current paper reviews the pathobiochemical properties of FQs, hints the directions for further research, and
reviews the research concerning the proposed treatment of patients. Based on the analysis of literature, the main directions of
possible effective treatment of FQAD are proposed: (a) reduction of the oxidative stress, (b) restoring reduced mitochondrion
potential ΔΨm, (c) supplementation of uni- and bivalent cations that are chelated by FQs and probably ineffectively transported
to the cell (caution must be paid to Fe and Cu because they may generate Fenton reaction), (d) stimulating the mitochondrial
proliferation, (e) removing FQs permanently accumulated in the cells (if this phenomenon takes place), and (f) regulating the
disturbed gene expression and enzyme activity.
1. Long-Term Adverse Reactions Caused by and their use becomes more restrictive and limited. FQs
Fluoroquinolones should be reserved for those who do not have alternative
treatment options.
Fluoroquinolones (FQ) belong to the group of broad- In 2016, the US Food and Drug Administration (FDA)
spectrum antibiotics, effective for both gram-negative and updated warnings, using next “black box” for oral and inject-
gram-positive bacteria. The most frequently prescribed drugs able FQs. The authors showed that FQs, when used systemi-
are ciprofloxacin (CIP), norfloxacin (NOR), and levofloxacin cally, are associated with disabling and potentially permanent
(LEV). FQs employ their antibacterial effect by preventing serious side effects. These side effects can involve the disrup-
bacterial DNA from unwinding and duplicating which takes tion of tendons, joins, muscles, nerves, nervous system dis-
place by inhibition of bacterial topoisomerase and gyrase. For turbances, and even induction of type 2 diabetes. Due to
the last three decades, FQs played an important role in treat- the increasing number of reports about FQ toxicity and
ment of serious bacterial infections, especially hospital- long-term complications, FDA has introduced significant
acquired infections. However, due to the possibility of serious restrictions on their use in recent years, particularly in chil-
side effects, these drugs are not currently first-line medicines dren and in people aged 65 years.
2 Oxidative Medicine and Cellular Longevity
1.1. Tendon Rupture. FQs are associated with a significant 1990–2012 and the increase in T2DM incidences in subse-
risk of tendonitis and tendon rupture. Stephenson et al. [1] quent years which suggests a large part of T2DM to be maybe
showed in their review the incidence of tendon injury among generated by FQ exposure.
those taking FQs to be between 0.08 and 0.2%. In 2014, Lewis
and Cook [2] proved that FQ-related tendinopathy is a 1.6. FQ-Associated Disability. In 2016, Kaur et al. [8] con-
complication of treatment with this family of antibiotics ducted basic science and clinical investigations of a newly
and it is usually linked with 1 or more synergistic factors: identified adverse drug reaction, termed FQ-associated dis-
male sex, age, renal disease, rheumatic disease, coprescrip- ability (FQAD). They proved that severe toxicities that
tion of corticosteroid, and physical activity. For this reason, develop when cancer patients receive supportive care drugs
some sport medicine specialists have advised avoidance of such as FQs are important, yet difficult to understand, detect,
FQs for athletes. Some authors, for example, [3, 4], proved and to communicate to clinicians. Their findings supported
that chronic renal disease, concomitant use of corticoste- recommendations of the FDA’s advisory committee. Revi-
roids, and age > 60 years are known risk factors for FQ- sion of FQ-product labels should be considered to include
induced tendinopathies. Concluding, FQs are associated prominent descriptions of a newly identified FQ-associated
with an increased risk of tendinitis and tendon rupture. This long-term toxicity.
risk is further increased in those over age 60, in kidney, Concluding, patients with impairments of the CNS (e.g.,
heart, and lung transplant recipients, and with use of con- epilepsy or arteriosclerosis), prolongation of the QT, elderly
comitant steroid therapy. persons, and individuals with concurrent use of glucocorti-
coids or chronic renal diseases should not be treated with
1.2. Nervous System Disturbances. Taking FQs is associated FQs. FQs are contraindicated in children because they cause
with their neurotoxicity as well [5–8]. The main symptoms destruction of the immature joint cartilage in animals. The
being correlated to FQ treatment include insomnia, restless- use in pediatrics is restricted to life-threatening infections.
ness, and, rarely, seizure, convulsions, and psychosis [9–11].
Many reports point to chronic persistent peripheral neurop-
athy to be generated by FQs [12–18]. Cohen [19] showed that
2. Oxidative Stress
a possible association between FQ and severe, long-term One of the main effects generated by FQs in cells is connected
adverse effects involving the peripheral nervous system as with the oxidative stress (OS). Thus, a brief review about OS
well as other organ systems is observed. is presented below.
The main aspect of OS involves the overdosed leakage of
1.3. Cardiotoxicity. Stahlmann and Riecke [20] showed that
electrons from the electron transport chain (ETC). In the
FQs prolong the heart’s QT interval by blocking voltage-
normal, healthy state, the Krebs cycle (KC) supplies hydro-
gated potassium channels. In some cases, this can be a
gen from glyco- and lipolysis in the form of NADH2 and
life-threatening condition because prolongation of the QT
FADH2 from KC to ETC. ETC separates hydrogen into
interval can lead to torsades de pointes, a life-threatening
protons and electrons. Protons are transported into mito-
arrhythmia. Statistically, significant risk factors for clinically
chondrial intermembrane space (IMS) generating proton
significant changes in QTs were hypokalemia and a left ven-
gradient, and mitochondrial membrane potential ΔΨm
tricular ejection fraction < 55%.
across the inner membrane and electrons is transported into
1.4. Hepatotoxicity and Nephrotoxicity. The other adverse oxygen. This complex process is a masterwork of the evolu-
reactions generated by FQs include hepatotoxicity [21] and tion because 4 electrons must enter the oxygen simulta-
nephrotoxicity [22]. Golomb et al. [23] reported a case- neously in order to produce 2 water molecules. In the case
series study and showed the potential occurrence of serious, of the block in the electron transport and the oxygen not to
persistent, and delayed multisymptom serious side effects be fully reduced in one step, the reactive oxygen species
apparently triggered by FQ use causing severe functional (ROS) are created, which might be able to generate OS.
compromise and disability in previously vigorous, healthy The total physiological electron leakage earlier estimated
individuals. In this study, Golomb et al. described patients to be about 1% of electrons supplied to ETC [25, 26] cur-
who developed new-onset symptoms during and following rently has been estimated in favourable conditions to be
FQ use. Domains of serious and persistent sequels included 0.1–0.5% in rest [27–29] and 0.01–0.03% in the exercise
the better-recognized tendon and muscle issues but extended [30, 31]. Assuming the oxygen consumption by the human
to the well-reported but still often unappreciated potential body in the rest to be about 500 g (which corresponds the
for cognitive, psychiatric, peripheral nervous, and gastroin- basal metabolic rate of 1920 kcal/24 h), the total electron cur-
testinal issues as well as endocrine issues. rent in all human mitochondria can be easily estimated to be
about 70 Amperes. The 0.1% leakage denotes the leakage
1.5. Diabetes Mellitus. Telfer [24] conducted interesting study electron current (LEC) to be about 0.07 Amperes. In the case
about FQ intake and development of type 2 diabetes mellitus of physical or mental exercise, both the metabolic rate and
(T2DM). They hypothesized that FQs induce an intracellular LEC increase several times; however, recent studies show that
Mg2+ deficit that can lead to insulin resistance. Their data LEC does not depend so strictly on the metabolic rate [30].
suggests that FQ exposure predisposes an individual to Disturbing the precise mechanism of electron flow through
develop diabetes. He also showed a strong correlation ETC causes nearly always the increased leakage which can
between the increase in FQ application in the US in years increase LEC even up to 10% (~7 A in the rest). Majority of
Oxidative Medicine and Cellular Longevity 3
toxins joining ETC may do this leak. Because the increased It consists mainly of voltage-dependent anion channel
OS is the side effect of the exercise state and OS is one of (VDAC), adenine nucleotide translocase (ANT), and cyclo-
the limits of the exercise, the increase in LEC during the rest philin D (CypD). In order to make the cell function prop-
may reduce the reserve for the OS increase during the exer- erly, the degree of the opening state of this complex must
cise. The patient may feel tired even during small physical be precisely fitted to the actual physiological state of the cell.
or mental exercise. If the complex is open, the nonselective traffic between the
O2− is the first oxygen radical created by LEC. Joining the IMS and cytosol of small-charged particles, water, and sub-
second electron causes the generation of H2O2, and joining stances up to 1.5 kDa takes place. ADP can enter mitochon-
the third electron to H2O2 creates a very dangerous hydroxyl dria to produce ATP but the protons leak from IMS to
radical OH∗ . H2O2 is relatively stable and works as a cellular cytoplasm reducing the mitochondrial potential ΔΨm from
sensor of the OS state and is involved in the cellular metabo- −140 mV to about −110 mV and contributing to apoptosis.
lism regulation [30, 32]. Brand [30] has recently detected 11 If the complex is closed, ADP cannot enter mitochondria
sites in ETC where electrons leak from ETC generating OS. to produce ATP and ΔΨm growths from −140 to
Brand and coworkers propose new postulate that the rate −160 mV. The decrease in ΔΨm is a characteristic for OS
of electron leak does not depend on the electron flow rate state, and the increase in ΔΨm is a characteristic for some
but on the redox state (electron pressure) of the given site types of cancers [32]. This observation explains the ability
of leakage. Thus, ETC blockers increase the leak in sites of FQs to treat cancers [36–41].
before the block and decrease the leak behind the block. The main factors that regulate PTP state [34] are as
Majority of the sites generate the leak to the mitochondrial follows:
matrix and only two sites to both sides of inner mitochon-
drial membrane: the sites IIIQo connected with complex III (a) Opening PTP
and GQ connected with glycerol 3-phosphate dehydrogenase
[30]. Brand et al. suggest also that the increase in O2− pro- (i) [Ca2+]mit: concentration of mitochondrial Ca2+
duction from complex III that signals hypoxia to the HIF- (ii) Reduced ΔΨm (positive loop)
1α signaling system in cells is probably caused by indirectly
changed metabolite concentrations that deliver more elec- (iii) Free radicals (oxidative stress)
trons to the ETC and leads to higher electron leak to oxygen.
(iv) Inorganic phosphate (only with Ca2+)
This is of high importance because as will be discussed later
in this paper, HIF-1α signaling is blocked in FQ patients dis- (v) Some apoptotic factors
turbing strongly very important energy production regula-
tory pathway. (b) Closing PTP
The last radical being created during the OS is OH∗ .
It is very dangerous because its lifetime is very short (i) Acidic pH (a part of cancer state is lactate accu-
(10−9 s) and the cell does not possess any enzymes remov- mulation in the cell)
ing it. The overdosed production of OH∗ is generated
especially by Fenton reaction or in the ischemia state in (ii) ATP, ADP and NADH
which, because of lack of the oxygen, all the electrons cre-
(iii) Mg2+
ate ROS. This massive ROS production induces the death
of the ischemic cell. Hexokinase II (HKII), mitochondrial creatine kinase
The relatively high physiological LEC forced the evolu- (CK), benzodiazepine receptor (PBR), and Bcl-2-family
tion to create the mechanisms carrying against free radi- members (Bcl-2, Bcl-xL, and Bax) are putative regula-
cals. The first and, thus, most important barrier is the tory components.
enzyme SOD2 (MnSOD, mitochondrial superoxide dis-
mutase) which annihilates O2−—the first molecule of the It can be observed that OS contributes to opening PTP
O2-radical chain (2O2− + 2H+ → O2 + H2O2). H2O2 is next and reducing ΔΨm. Reduced ΔΨm causes further opening of
removed by catalase or glutathione peroxidase. Meanwhile, PTP and the decrease in energy production. The final step
it comes out of mitochondria and regulates, for example, and physiological sense of this positive loop are the induction
redox-dependent Kv1.5 channels in the cell membrane of the apoptosis. However, if the apoptosis induction is not
[32]. This mitochondrion-ROS-Kv channel axis is now rec- reached, the new balance between factors being in the com-
ognized as basis of an important O2-sensing mechanism in mon regulatory loop finds a new equilibrium point which
many tissues [33]. can be far away from that optimal one. The “positive loop”
The simplified scheme of the electron leakage from ETC regulation of PTP points to its high sensitivity to different
is presented in Figure 1. factors controlling it and suggests the regulation of PTP to
be one of the most important points of energy production
2.1. The Role of Mitochondrial Permeability Transition Pores control. Some positive regulatory loops are presented in
(PTP) in the Regulation of Energy Production. The mito- Figure 2. According to the control theory, such positive loops
chondrial permeability transition pore (PTP) is a large denote that the reaction to small stimulus may be strongly
protein complex placed in the outer mitochondrial mem- magnified. The influence of FQs on the detailed regulation
brane being precisely regulated by many factors [34, 35]. of PTP is the urgent topic for further research.
Acetylo-CoA
KC
H2O2 H2O
Hydrogen pressure
4e‒ + O2 ATP
NADH2/NAD 1e‒ + O2 O2‒
e‒ e‒ e‒ e‒
ATP synthase
e‒ H+ ADP + P
1e‒ + O2 O2‒
O2‒/H2O2
H2O2 CA2+
Norm OS (open PTP) Δ훹m

Δ훹m: ‒140 mV ‒110 mV PTP open Main opening inducers
H2O2
efflux
H+
Figure 1: The schematic presentation of the ATP production system. The acetyl-CoA supports Krebs cycle to produce NADH2. Hydrogen
from NADH2 (and FADH2) enters the cytochrome chain. Some electrons leak before they reach oxygen generating O2− and next H2O2. H2O2
comes away from mitochondria and works as a redox signaling molecule. The amount of leaking electrons depends mainly on NADH2/NAD
ratio (hydrogen pressure). The degree of PTP opening must be precisely regulated and depends on many factors, for example, O2−/H2O2, Ca2+,
and ΔΨm.
2.2. How the Cell Adapts to OS State. Increased OS state is The escaping K+ increases temporarily the negative potential
characterized first by increased H2O2 level in the cell. In the inside the cell. It can be concluded that restoring the negative
physiological state, H2O2 level informs the cell and nucleus cell potential is more important for the cell than keeping high
about the mitochondrial energy production state because, K+ concentration in the cell.
in the physiological conditions, it is connected with the met- On the other hand, in the case of reduced ATP produc-
abolic rate of the cell. In the case of disturbed metabolic reg- tion, the lowered ΔV opens voltage-gated Ca2+ channels
ulation (e.g., mitochondrial toxins), increased OS and open which causes Ca2+ influx into the cell [32]. Increased [Ca2
+
PTP, ATP production is reduced. The main process that con- ]i activates calcineurin. Activated calcineurin shifts NFAT
sumes ATP in the cell is the Na/K pump that removes Na+ (nuclear factor of activated T-cells) to the nucleus where it
from the cell, pumps K+ to the cell, and generates the negative inhibits Kv1.5 potassium channel production. Lowered
membrane potential of the cell. The work of Na/K pump is amount of Kv1.5 channels reduces K+ efflux. Concluding,
the most fundamental process of life because it consumes in the OS state, Kv1.5 channels are more open; however, their
20% to 50% of ATP and generates strongly negative charge amount is reduced. Two opposite mechanisms regulating the
inside the cell. Many other transports that take place across membrane potential and K+ efflux find some new equilib-
the cell membrane work as Na+ cotransport, for example, rium. This mechanism seems to be the natural adaptation
amino acids, phosphates, Ca2+, and boric acid. One molecule process to the increased metabolic rate of the cell generating
of Na+ cotransport contributes to about 30% of ATP/ADP physiological OS. In the state of increased metabolic rate, the
Gibbs free energy; thus, it can be treated as “small energy concentration of K+ (and most probably Mg2+) is reduced,
bricks” when compared to ATP as a large one. The lack of the concentration of Ca2+ and H2O2 (and most probably
ATP reduces the work of Na/K pump reducing negative Na+) is higher, and the membrane potential is also reduced.
membrane potential ΔV and K+ concentration in the cell. If the healthy cell returns from the increased metabolic
However, H2O2 generated during OS activates the opening rate to the resting state, all these parameters return to their
of redox-dependent Kv1.5 channels in the cell membrane optimal values. This return depends on the ability of the
[32] contributing to the further efflux of K+ from the cell. mitochondria to produce ATP which drives Na/K pump.
Organopathiae
HIF-1훼
FQs ?
PDH Accelerated
aging
NADH2
Fenton
? reaction
+?
O2‒/H2O2 leak Cytochrome
Metal chelation mutation
+ + +?
?
Open PTP mtDNA damage
DNA/histone Disturbed collagen +
methylation hydroxylation Δ훹m + NO ONOO‒
Reduced gene Tendinopathy +?
[Ca2+]i iNOSmt
expression arthropaty ATP
+
ΔV
Unknown Tiredness + : Positive regulatory loops

effects weakness magnifying the toxicity of FQs
Figure 2: The main ways of FQ toxicity. The positive regulatory loops magnifying the toxicity of FQs are marked with “+.” The “?” signs
denote the possible but not confirmed effects of FQ toxicity.
In the case of the permanent OS or disturbed state of PTP in the cytoskeleton were observed also after FQ treatment
being inadequately open, this return cannot take place [45], and cytoskeleton has been demonstrated to be strictly
because the ATP production is lowered. The cell being in connected with energy dissipation and organization in mito-
the resting state comes to the state which can be called “per- chondria [46–49]. The most important elements of FQ toxic-
manent stress adaptation.” In the case of the necessity to ity are presented in Figure 2. The positive regulatory loops
increase the metabolic rate, further increase in metabolic rate magnifying the toxic effects are marked with “+.” Let us ana-
is difficult because of the lack of physiological adaptation lyze the most important aspects of the molecular activity of
reserve. The final effect for the patient is the feeling of “the FQs in the cell, being reported until now.
lack of energy.” Many other regulative processes take place,
of course, as OS adaptation. However, the above-described 3.1. Chelating Bivalent Cations and Proteins by FQs. FQs are
changes belong in authors’ opinion, to the primary regula- the group of chemical compounds called zwitterions. Zwit-
tory axes. terion is a neutral molecule with both positive and negative
electrical charges on its opposite sides. This feature makes
3. Molecular Mechanisms of FQ Toxicity them possible to create strong complexes with both protein
anions and positively charged bivalent cations. The proton-
Good understanding of the OS state is very important for ation constants for the acidic and base part of the FQ mole-
understanding the consequences of OS generation by FQs. cules were estimated as pK1 = 8.2–8.5 and pK2 = 5.6–6.2.
From the therapeutic point of view, the important question These values denote that the dissociation coefficients are
concerns the molecular mechanisms leading FQs to generate equal to about 90–95% in neutral intracellular conditions of
OS, because they determine the possible effective treatment pH = 7.0 for both the acidic and base side of the molecule
of this state. Many people are waiting for the understanding [50]. The structure of the exemplary FQ is presented in
of the FQ toxicity mechanisms and treatment methods. Figure 3.
Beside OS, epigenetic effects of FQs are of high importance FQs possess two main sites for metal chelate formation.
as well. The epigenetic effects may depend on the methyla- The first one, represented by the carbonyl and carboxyl
tion of DNA and/or histones; however, ROS contribute also groups in neighboring positions, is the most common coordi-
to epigenetic changes [42]. Some authors point also to the nation mode in the quinolone chelates [50]. Quinolones bind
similarity of bacterial and mitochondrial DNA, both existing divalent cations as Mg2+, Ca2+, Cu2+, Zn2+, Fe2+, and Co2+,
in circular super-twisted helices and gyrase-like enzymes forming chelates with 1 : 1 or 1 : 2 metal : FQ stoichiometry
being postulated to be responsible for the organization of or trivalent cations (e.g., A13+ and Fe3+), forming chelates
mitochondrial DNA, suggesting the possible direct effect of with 1 : 1, 1 : 2 or 1 : 3 metal : FQ stoichiometry. The constant
FQs to mitochondrial DNA leading to the disturbed mito- values for CIP chelates have been measured to decrease in the
chondrion regeneration and division [43, 44]. The changes following order: Al3+ > Fe3+ > Cu2+ > Zn2+ > Mn2+ > Mg2+
O O Metal ion chelating seems to be the most fundamental

feature of FQs which probably leads to all other observed
F toxic effects. The antibacterial effect is connected with chelat-
‒ ing Mg2+ which disturbs the gyrase and topoisomerase inter-
O
action with DNA. However, the Mg2+ is described to create
weaker chelates with FQs than other important ions like
Fe2/3+, Cu1/2+, Zn2+, and Mn2+.
N N The well-described activity of FQs which concerns the
Fe3+ chelating was examined by Badal et al. [56]. They
examined that three FQs, NOR, CIP, and enrofloxacin
NH2+
(ENR), are the powerful Fe2/3+ chelators comparable with
Norfloxacin deferoxamine, a clinically useful Fe-chelating agent. He
showed that Fe2/3+chelating by FQs leads to epigenetic
Figure 3: The exemplary FQ—norfloxacin and its zwitterion effects through inhibition of α-dependent dioxygensases
structure. (DOXG) that require Fe as a cofactor. Three important
DOXGs were analyzed: jumonji domain histone demethylase,
TET DNA demethylase, and collagen prolyl 4-hydroxylase.
[51]. For NOR chelates, the relation is quite similar: The activity of all 3 enzymes was reduced by FQs in micromo-
Fe3+ > Al3+ > Cu2+ > Fe2+ > Zn2+ > Mg2+ > Ca2+. Let us observe lar concentrations leading to accumulation of methylated his-
that presented research [50, 51] did not analyze Se2+ ions tones and DNA and to inhibition of proline hydroxylation.
which are also of high importance in the cell, because Se2+ The IC50 concentrations for Fe-chelation were equal to about
is the cofactor of glutathione peroxidase removing H2O2. 52 ± 20 uM for CIP, 44 ± 15 uM for NOR, 41 ± 20 uM for
The examination of the ability of FQs to generate Se2+-FQ ENR, and 360 ± 25 uM for deferoxamine. These results point
complexes is the important aim for further research. to high ability of FQs to absorb Fe2/3+ and reduce the activity
Seedher and Agarwal [52] analyzed the ability of 5 cat- of enzymes which use Fe2/3+ as a cofactor. The results suggest
ions: Fe3+, Al3+, Zn2+, Cu2+, and Mg2+ to create the com- also the possibility that the tendon FQ toxicity is dependent
plexes with four FQs and human serum proteins using on lack of collagen proline hydroxylation which changes
fluorescence UV absorption spectroscopy. They measured significantly the mechanical properties of the collagen.
the association constants to be of the order of 102–104 for Some other studies report, however, the association of the
the FQ-Men+ interaction. The interaction was the highest enhanced extracellular matrix metalloproteinases [51, 52],
for Al3+ and lowest for Mg2+. At a Men+/drug ratio of 1 : 1, mainly collagenases expression [53], to be associated with
approximately 50%–73% of metal ion was bound per mole FQ-induced tendinopathy.
drug in most cases. Seedher’s results indicate that chelate for- It must be pointed that cytochromes are the other
mation with bivalent metals can cause significant alteration important proteins which use Fe2/3+ in hem groups as a
in the human serum-FQ-binding affinity. cofactor. Thus, the question arises if the reduced free Fe2/3+
Koga [53] measured the FQ concentration ratio between concentration in the cell contributes to ETC inhibition, elec-
intra- and extracellular fluid in human polymorphonuclear tron leakage, and/or OS. The question arises, as well, which
leukocytes using high-performance liquid chromatography. cellular effects are connected with Cu2+ and Zn2+ ions,
This ci/cout ratio oscillated between 2.2 to 8.2. In another because Cu+ is also an important cytochrome cofactor and
paper, Pascual et al. [54] presented ci/cout gradient for trova- Zn2+ is important due to high number of enzymes (about
floxacin (TRV) to be about 9 for extracellular concentrations 300 total) being cofactored by this element and the total cyto-
ranging from 0.5 to 25 ug/mL. Assuming net charge of the plasm concentration of Zn2+ is similar and even higher than
FQ molecules being close to 0, the expected ratio for the sol- that of Fe2/3+. Valko et al. [57] present that redox-inert zinc
uble fraction is expected to be close to 1 : 1. These results (Zn2+) is the most abundant metal in the brain and an essen-
point to the ability of FQs to create complexes with different tial component of numerous proteins involved in biological
intracellular molecules which do not participate to the solu- defense mechanisms against oxidative stress. The depletion
ble fraction of FQs in the cell. of zinc may enhance DNA damage by impairing DNA repair
The other important feature of FQs has been presented mechanisms.
by Andriole et al. [55]. Namely, they estimated the minimum Some effects of Mg2+ chelation are also well described,
solubility of FQs in neutral pH. They pointed that this especially with respect to the cartilage damage. Mg2+ is an
class of molecules is characterized by very high melting important intracellular ion being a cofactor of about 300
point, generally > 200°C, which indicates that the crystal enzymes. Shakibaei et al. [58] showed that effects of individ-
forms are very stable. ual dose of ofloxacin give identical effects in cartilage
All these FQ features strongly support the thesis that observed in electron microscopy as Mg2+-deficient diet sug-
FQs can survive in the cell for a long time contributing to gesting that quinolone-induced arthropathy is probably
chronic, long-term adverse reaction in patients treated with caused by a reduction of functionally available Mg2+ in carti-
FQs. The question, to what extent this phenomenon takes lage. Similar results were observed during cultivation of
place and if it contributes to chronic symptoms of FQAD, chondrocytes in Mg-free medium [45, 59–61]. The supple-
remains unclear. mentation of Mg2+ accompanying the FQ treatment restored
to some degree the cartilage lesions [60, 61], however, did not strongly reduced at concentrations 1 mM (100x higher than
restore the reduced cell division [61]. This suggests that other therapeutic ones). ROS production has increased slightly
mechanisms are involved in cell division reduction after FQs (~25%) but significantly at therapeutic conditions and
[44]. Mg2+ deficiency in immature dogs induced similar clin- strongly (~150%) at 100 uM (10x higher than therapeutic
ical symptoms as quinolone treatment: distinct alterations in ones). The intracellular GSH concentration was reduced
chondrocytic fibronectin staining and their ultrastructure by 20–50% even at 0.01 uM concentrations (1000x smaller
[62, 63]. The effect of Mg2+ supplementation had a two- than therapeutic ones), and the collapse (decrease in 50–
way effect on FQ-treated cultured chondrocytes: the num- 90%) in GSH was observed at 1 mM. The question arises
ber of cells adhering to culture support was increased and if the GSH depletion is connected only with the increased
cell morphology was comparable to that of control cells. H2O2 generation or also with a reduced activity of GSH-
This suggests that addition of Mg2+ restores extracellular reductase which restores the reduced form of GSH
Mg2+-dependent intercell interactions. (GSSG + NADPH2 → 2GSH + NADP).
On the other hand, dietary Mg2+ is also presented to It is important to observe that the rapid increase in the
reduce intestinal FQ absorption [64–70] and it is also toxicity takes place after the given concentration of FQs is
postulated to be in relation to diabetes type 2 and FQ reached which is only slightly higher than the therapeutic
treatment [24]. one. The substantial increase in the ROS production which
Summing up, the number of enzymes possessing reduced can lead to serious consequences begins at concentrations
activity due to their ion-cofactor chelation is probably long being approximately 10x higher than that of the therapeutic
and it is the important topic for further research. The sepa- ones. This factor is, however, estimated with low precision
rate problem consists the chronicity of ion chelation by because no intermediate concentrations were examined
FQs. The presented research does not describe the chronic between 0.01, 0.1, 1, 10, 100, and 1000 uM. Assuming that
state of FQAD but the phenomena taking place during FQ some people are charged with reduced ROS annihilation abil-
application. It must be analyzed as to which degree persistent ity (e.g., as presented in [21]), this toxicity limit may occur at
ion chelation takes place at FQAD patients. lower, therapeutic concentrations. This experiment stays also
in the agreement with clinical observations that the FQAD
3.2. Oxidative Stress Generated by FQs. Many papers point takes place especially in patients who were treated with
to the feature of FQs to generate oxidative stress in the higher FQ doses, by a longer period or with FQ series
cells. The molecular mechanisms leading to OS state differ repeated a few times in a short period of time.
probably in details for different FQs depending on different In the other paper, Pouzaud et al. [74] observed in vitro
abilities to chelate subsequent metal ions and on possible in rat tendons the increased ROS production and reduced
different abilities to change enzyme activity in the ion- GSH concentration. Similar results were also showed by
independent manner. Yu et al. [72].
An example of ion-independent FQ activity was pre- Some papers point to detailed FQ effects on different
sented by Qin and Liu [71]. They analyzed the influence of enzymes. Hsiao et al. [21] found that TRV-induced OS on
CIP and ENR on the erythrocytic catalase (CAT), a vital heterozygous SOD2 (+/−) deficiency mice was higher than
enzyme involved in OS reduction (CAT reduces H2O2 to on the normal mice. Hepatic protein carbonyls were
O2 and H2O). The cellular tests firstly confirmed an increased by 2.5-fold, and hepatic mitochondrial aconitase
enhanced oxidative stress in FQ-treated erythrocytes in the activity was decreased by 20% in mutant, but not in wild-
form of the GSH content depletion and decrease in CAT type mice. Because aconitase is a major target of peroxyni-
activity with CIP effect to be more harmful than ENR. Next, trite, they determined the extent of nitrotyrosine residues in
spectroscopic computations showed the FQ-binding places hepatic mitochondrial proteins (peroxynitrite ONOO− id
to CAT takes place mainly through electrostatic forces. Bind- formed by the combination of O2− and NO). TRV signifi-
ing of two FQs not only caused the conformational and cantly increased nitrotyrosine in SOD2 (+/−) mice only.
microenvironmental changes of CAT but also inhibited its TRV increased also the production of mitochondrial NO in
molecular activity, which was consistent with the cellular immortalized human hepatocytes. Similarly, mitochondrial
activity measurements. On the other hand, the treatment Ca2+ was increased by TRV, suggesting Ca2+-dependent acti-
with danofloxacin [72] increased antioxidant enzyme activi- vation of mitochondrial NOS activity. Furthermore, the tran-
ties such as superoxide dismutase (SOD) and catalase script levels of the mtDNA-encoded gene Cox2/mtCo2 were
(CAT), suggesting that the ability of subsequent FQs to decreased in SOD2 (+/−) mice only, while the expression of
change the activity of different antioxidative enzymes can nDNA-encoded mitochondrial genes was not significantly
vary significantly. altered in both genotypes, suggesting selective effects on
Many papers present the existence of OS induced by FQs, mtDNA expression. These data indicate that TRV enhances
for example, Pouzaud et al. [73] measured the redox status hepatic mitochondrial peroxynitrite stress at increased basal
change of immortalized rabbit tendon cells as a response to O2− levels, leading to the disruption of critical mitochondrial
pefloxacin, ofloxacin, LEV, and CIP. All FQs showed moder- enzymes and gene regulation.
ate cytotoxicity on tendon cells after 24 h and more severe, Another important information can also be found in
significant toxicity after 72 h. The intracellular redox poten- [21]. OS generation by FQs may take place at lower FQ
tial has been reduced slightly but significantly after 72 h even concentrations in some people being charged with lower
at concentrations 1 uM (~10 uM is the therapeutic one) and ability to reduce OS. The reasons of reduced OS barrier
may be different; however, the most important reasons One of the proteins which can support PTP opening is
seem to be the heterozygous mutations, trace element defi- translator protein (TSPO), called also peripheral-type ben-
ciencies, and charge of the cells with other toxins contrib- zodiazepine receptor or isoquinoline-binding protein.
uting to OS. TSPO is predominantly located on the surface of the mito-
Kumbhar et al. [75] reported gatifloxacin (GAT) to pro- chondria where it is postulated to physically associate with
duce retinal damage in rabbits and significant alteration in VDAC-ANT. It has been suggested that TSPO may activate
the antioxidant status indicated by the decreased activity PTP opening, causing ΔΨm reduction and leading to apo-
of superoxide dismutase and decreased levels of blood gluta- ptosis [80, 81].
thione with a concomitant increase in the activity of cata- Some authors suggest that epileptogenic activity of FQs
lase, glutathione peroxidase, and glutathione S-transferase possibly relates to GABA-like structure of some FQs which
enzymes. The levels of malondialdehyde were also elevated. may allow them to act as GABA antagonists [82, 83]. Since
The effects were dose-dependent. Talla and Veerareddy [76] TSPO is also a benzodiazepine receptor, similar interaction
examined the OS parameters in the blood after CIP, LEV, may maybe also take place between FQs and TSPO leading
and GAT therapy on SOD3 (extracellular), glutathione, to opening PTP.
plasma antioxidant status, and lipid peroxides evaluated at The problem of the PTP opening is probably, however,
53 patients on different dosage regiments up to 5 days. more complicated and it is in relation with many other fac-
The significant elevation of lipid peroxide was observed in tors involved in energy production and apoptosis induction
patients treated with CIP and LEV. The substantial deple- in the cell. The broad reviews about regulation of PTP and
tion in SOD3 and glutathione was observed especially in VDAC (the main PTP protein) are presented in [34, 35].
CIP patients. All three FQs reduced the plasma antioxidant The other way to reduce ΔΨm is the opening of UCP
status, but especially CIP and LEV. channels which generate the proton leak through the inner
Liu et al. [77] determined the effect of ENR on the release mitochondrial membrane. UCP regulation is a separate
of lactate dehydrogenase (LDH), reactive oxygen species problem and possible way for treating FQAD patients. The
(ROS), superoxide dismutase (SOD), total antioxidant capac- review of this problem is published by Divakaruni et al. [84].
ity (T-AOC), malondialdehyde (MDA), mitochondrion
membrane potential (ΔΨm), and apoptosis in the hepatic cell 3.4. Does Fenton Reaction Take Place in FQAD Patients?
line of grass carp. The doses of 50, 100, and 200 ug/mL The next problem that is connected especially with Fe2+
increased the LDH release and MDA concentration, induced and Cu+ ions is the possibility of the Fenton reaction (FR)
cell apoptosis, and reduced the ΔΨm compared to the control. to be generated on Fe2/3+ and Cu1/2+ ions, but maybe on
The highest dose of 200 ug/mL also significantly reduced the FQ-Fe2+ complexes as well. Fenton reaction consists in
T-AOC. the conversion of O2− and H2O2 into strongly dangerous
All the above-presented experiments show the increased OH∗ radical; it takes place on Fe2+/3+ and Cu1+/2+ ions and
OS state after FQ treatment. The changes in enzyme activity consists of 2 steps:
vary between experiments, tissues, and kinds of FQs suggest-
ing possible variability of the common relations. What seems (1) Fe2+ + H2O2 → Fe3+ + OH∗ + OH−
to be important is the reduction in SOD activity which is the (2) a. Fe3+ + O2− → Fe2+ + O2 or (2) b. Fe3+ + H2O2 → Fe2+
first-line barrier against O2−. New experiments must estimate + O2− + 2 H+
these changes in details; however, more attention must be
paid to mitochondrial MnSOD which cares against mtDNA This reaction increases strongly the effects of OS in the
damage by O2− generated by leaking electrons from ETC to cell and if it is too intense, it may contribute to cell death.
mitochondrial matrix. The increased activities of some anti- The question arises as to what degree does the Fenton reac-
OS enzymes seem to be the OS adaptation processes. tion magnify initial OS effects.
There is no evidence that would prove such reaction to
3.3. Reduction of Mitochondrial ΔΨm Potential by FQs. One take place in FQAD patients; however, four theses could be
of the cellular symptoms present in the FQ-charged cells is postulated for further research: (a) The reaction is increased
the reduction of the mitochondrial potential ΔΨm [37, 38, just due to the increased substrate concentration (O2− and
77–79]; however, the detailed mechanism of this phenome- H2O2) for FR. (b) The reaction intensity is reduced with
non remains unknown. Since the main mitochondrion respect to that expected due to the reduced Fe2+ level in the
uncoupling factor is the PTP, the reasons of the reduced cell. This can take place due to reduced membrane potential
ΔΨm should be searched between factors that regulate PTP and reduced ability Fe2+ to be pulled into the cell. (c) The
opening. The first possibility is the OS by itself being gener- reaction is magnified due to the increased ability of FQ-
ated by FQs. ROS can induce VDAC oligomerization (the Fe2+ complexes to generate OH∗ in FR reaction by itself.
main part of PTP) to yield a megachannel creation which (d) The reaction is magnified due to upregulation of Fe-
are postulated to create large holes being able to release cyto- transporting protein which increases Fe2+ concentration in
chrome c to cytoplasm. O2−-induced apoptosis has been the cell. Similar upregulation has been detected in Streptococ-
found to be inhibited by DIDS or anti-VDAC antibodies cus pneumoniae by Ferrandiz and de la Campa [85, 86]. They
(VDAC blockers), which suggests that O2− increases observed the upregulation of the genes of the fat DCEB
VDAC-dependent permeabilization of the outer mitochon- operon involved in iron (Fe2+ and Fe3+) uptake. In accor-
drial membrane [80, 81]. dance, they observed an attenuation of LEV lethality in
iron-deficient media. However, the bacterial gene regulation biotransformation in the liver from approximately 50 percent
cannot be directly compared to that mammalian one. On for pefloxacin to about 6 percent for ofloxacin [91]. Although
the other hand, electro-Fenton reaction is described to glucuronide conjugates have been identified as minor metab-
perform degradation of LEV in experimental conditions olites for some agents, most metabolic reactions involving
[87, 88]; however, it seems to be of low probability for quinolones occur through microsomal oxidative mecha-
such reaction to take place at in vivo conditions. nisms at the cytochrome P-450 site. These metabolic alter-
ations involve the piperazinyl moiety and usually result in
3.5. Changes in Gene Expression and Enzyme Activities after compounds with significantly less microbiologic activity than
FQ Treatment. Besides OS aspects connected with FQAD, the parent drugs. However, the conclusions from fish cannot
some papers point to other effects of FQ toxicity. Fox et al. be directly transferred to humans and the results suggest the
[89] measured reverse-transcriptase quantitative polymerase possibility of the delayed toxicity to be connected with
chain reaction analyses on total RNA isolated from supraspi- reduced detoxification induced by itself.
natus tendon of rats. They showed the significant upregula- Similar results of P-450 inhibition by FQs were found
tion of IL-1b mRNA, tumor necrosis factor (TNF), matrix in chicken by Shlosberg [92] and Granfors et al. [93].
metalloproteinases MMP-3 (30x increase), MMP-13 (7x), Regmi et al. pointed to the inhibiting effect of FQs in dogs
and the tissue inhibitor of metalloproteinases- (TIMP-) 1 on P-450 1A but not on P-450 3A [94, 95].
(4x) in the FQ-treated rats. FQ-treated groups showed signif-
icantly less fibrocartilage and poorly organized collagen at 3.6. FQs and HIF-1α. Dioxygenase inhibition by FQs was
the healing enthesis compared with control animals. predicted by Badal et al. [56] to stabilize transcription
Aranha et al. [41] measured the gene expression effects factor HIF-1α by inhibition of the oxygen-dependent
of CIP on prostate carcinoma and healthy control cells. hypoxia-inducible transcription factor prolyl hydroxyl-
Treatment of prostate cancer cells with CIP resulted in a ation. In dramatic contrast to this prediction, HIF-1α pro-
dose- and time-dependent inhibition of cell growth (70– tein was eliminated by FQ treatment. Badal and coworkers
100% with 50–400 ug/mL). Cells were arrested at the S explored this effect to be caused by inhibition of HIF-1α
and G2/M phases, and apoptosis was induced. The mRNA translation.
cyclin-dependent kinase (CDK) inhibitor p21/WAF1 was The natural function of HIF-1α system is to change the
downregulated 12 h following CIP in treatment which metabolism of the cell into the anaerobic pathway in order
can lead to rapid CDK2 activation and caspase-induced to protect the cell against OS. The conversion of pyruvate
apoptosis. There was also observed significant increase in to lactate is enhanced by upregulation of the lactate
the Bax/Bcl-2 ratio with translocation of proapoptotic dehydrogenase-A (LDH-A). On the other hand, pyruvate
Bax to mitochondria and activation of caspase-3. Let us dehydrogenase complex is inhibited by HIF-1α by upregu-
recall that Bax, Bcl-2, and capsace-3 are involved in PTP lating pyruvate dehydrogenase kinase (PDK) which inhibits
opening state. PDH-A. Thus, HIF-1α inhibits pyruvate to enter KC and
Badal et al. [56] showed that NOR, CIP, and ENR as iron to produce NADH2. As presented by Brand et al. [96],
chelators lead to epigenetic effects through inhibition of NADH2/NAD ratio (which can be called “hydrogen pres-
alpha-ketoglutarate-dependent dioxygenases that require sure”) is the main factor determining the escape of electrons
iron as a cofactor. Three dioxygenases were examined in from the ETC chain, making this process to high degree
HEK293 cells treated with FQ. At micromolar concentra- independent of the total ETC electron flow. (The term
tions, these antibiotics inhibited jumonji domain histone “hydrogen pressure” reflects the natural similarity of ETC
demethylases, TET DNA demethylases, and collagen prolyl to the water flowing through the pipe with small holes.
4-hydroxylases, leading to the accumulation of methylated The water escaping through the holes depends on the pres-
histones and DNA and inhibition of proline hydroxylation sure but not on the water velocity in the pipe.) Thus, in case
in collagen. These effects may explain FQ-induced nephro- of the lack of the oxygen in the tissue which is the final recip-
toxicity and tendinopathy. Let us observe that the changes ient of the electrons from NADH2, HIF-1α turns on the side
in DNA and histone methylation state cause strong and way for hydrogen, not to put it into ETC and produce OS
broad epigenetic effects being difficult to predict. but to produce lactate. The lack of this safety valve (HIF-
Liang et al. [90] measured the subchronic toxic effects of 1α) in FQ patients may cause the shift of the overdosed
NOR on a swordtail fish by measuring mRNA expression of amounts of hydrogen into ETC causing overdosed electron
cytochrome P450 1A (CYP1A), cytochrome P-450 3A leak. Assuming this phenomenon to be important in FQ-
(CYP3A), glutathione S-transferase (GST), P-glycoprotein treated patients, the glyco- and lipolysis inhibitors could be
(P-gp), and their corresponding enzyme activities. Results considered as OS reductors. The natural glycolysis inhibitor
showed that NOR significantly affected the expression of in the diet is citric acid which inhibits phosphofructokinase
CYP1A, CYP3A, GST, and P-gp genes in swordtails. The (the main regulatory point of glycolysis) and activates fruc-
gene expressions were, however, more responsive to NOR tose 1.6 bisphosphatase which catalyzes the opposite reaction
exposure than their corresponding enzyme activities. The promoting gluconeogenesis and pentose cycle pathway. On
analyzed enzymes are very important because they express the opposite, the vinegar (acetic acid) could be contradicted
the ability to catalyze detoxification of xenobiotic substrates, by FQAD patients because it promotes glyco- and lipolysis
including FQs. The possible reduction of its activity in both contributing to possible overdosed “hydrogen pressure”
humans may be of high importance, because FQs undergo and OS.
4. Therapeutic Conclusions Table 1: The conversion of Nernst equation cin /cout = exp ΔV zF/
RT for bivalent ions as Mg2+, Mn2+, Fe2+, and Zn2+ shows strong
The treatment of the FQAD, especially that lasting for many relation between the actual membrane potential and ability of
years, is a very difficult therapeutic problem. The effective- the cell/mitochondrium to attract and absorb the ions into the
ness of different therapies carried out on patients is rather cell/mitochondrium. Reduced membrane potential ΔV is a
strong factor which hinders entering bivalent cations to the cell.
low. A large number of patients suffers from chronic tired-
However, the detailed mechanisms of individual ion transport
ness, tendinopathies, neuropathies, and lack of sleep, even must be analyzed.
more than 12 h/24 h. Understanding all the molecular mech-
anisms of the FQ activity in the cell is the urgent aim for the ΔV/ΔΨm Equilibrium cin/cout gradient (z = 2 and T = 310 K)
current science to find methods helping these people. −160 mV 160.000x
The main question that arises here concerns the reasons
−140 mV 36.000x
of chronicity of FQAD symptoms which last for many years,
−110 mV 3.800x
sometimes, even after a standard 5-day FQ treatment. 3 rea-
sons can be taken into consideration: −90 mV 850x
−70 mV 190x
(a) Long-lasting OS destroys the mitochondrial DNA −50 mV 42x
and the newly synthesized proteins creating cyto- −30 mV 9x
chrome complexes are disturbed in their structure
leading to permanent electron leakage and OS.
to the negative value of mitochondrial potential ΔΨm. The
(b) The complexes of FQ with proteins and cations are Nernst equation ΔV = RT/zF ln cin /cout defines the equilib-
so stabile that they exist in the cells by many years rium between the ion concentration gradient and voltage
disturbing energy production and epigenetics. across the membrane. If the membrane voltage ΔV/ΔΨm
(c) Epigenetic changes in gene regulation become persis- decreases, the concentration equilibrium gradient cin/cout of
tent many years of FQ application even in the case of bivalent ions decreases significantly as well, because the low-
lack of FQ in the cell. ered potential may not be able to pull bivalent cations into
the cell/mitochondrium up to the required concentration.
The answer, which of these three possible reasons con- Table 1 shows the exemplary calculations.
tribute to the chronicity of FQAD symptoms, is of high Table 1 shows that the decrease in membrane voltage
importance with respect to the problem of effective treatment reduces strongly the ability of the cell to pull X2+ ions into
of this state. The research answering these questions must be the cell/mitochondrium. The question arises as to what
performed as fast as possible. extent the transport of X2+ ions into the cell is disturbed in
In the case of mtDNA destroying, the treatment is diffi- FQAD patients. And next, if the possible lower X2+ concen-
cult and it must focus on the stimulation of mitochondrial tration depends only on reduced ΔV/ΔΨm or maybe also
replication. The more destroyed mitochondria must be on the disturbed membrane transport being blocked by FQs
removed and the less destroyed must replicate in order to joining to metal-binding sites of transport proteins? Every
substitute for the removed ones and to reduce the total analyzed bivalent cation requires a separate analysis.
LEC. After many replications, the most healthy mitochondria The third possible reason of the permanent FQAD state is
would dominate the cell. The final effect would depend on the permanent disorder in gene expression caused by some
the state of the most healthy mitochondrium in the cell. positive loop regulations. For example, reduced Fe2+ level
The second possibility is to increase the ratio of cell exchange disturbs oxoglutarate-dependent dioxygenases and increases
in the given tissue. The cells with more destroyed mitochon- methylation of DNA and histones which leads to reduced Fe2
+
dria must be shifted to apoptosis while more healthy cells absorption to the cell. Many other loops are possible which
must substitute them. This process, however, cannot take could cause the chronic state of the patient despite the lack of
place in the central nervous system and muscles because FQs in the cell. They have to be recognized in order to find
the cell exchange is close to zero in these tissues. Also, the col- the methods restoring the normal regulatory state. This case
lagen exchange is very low causing the tendon regeneration is the most hopeful for patients, because, for example, the
to be a difficult and long-lasting problem. mtDNA damage is rather difficult to be effectively treated
If new research would confirm the existence of FQs in the and gene expression regulation is difficult, however, possible.
cells and mitochondria in the amounts making possible their Until detailed knowledge concerning FQ toxicity would
permanent interactions with proteins and cations even after be recognized, the following directions in supporting FQAD
many years of FQ application, the research must focus on patients are proposed according to the known and probable
methods on how to remove FQs from strong protein and cat- mechanisms of FQ toxicity:
ion complexes. The simplest way seems to be the application
of increased doses of metal cations Fe2+, Cu+, Mn2+, Zn2+, (a) Reduction of the oxidative stress: assuming that H2O2
and Mg2+ which are natural FQ-competitors for protein- is not effectively removed from the cell after FQ treat-
binding sites. It should be pointed that bivalent metal ions ment, subsequent consequences may occur such as
enter the cell to some degree due to the negative membrane opening Kv1.5 channels, Fenton reaction, peroxy-
potential of the cell and, next, enter the mitochondria due nitrite radical creation, opening PTP channels,
decoupling mitochondrial potential, and, finally, able to close PTPs [102, 103] and protect against
breaking down OS barrier. The detailed compari- OS [102, 104–106]; thus, it is an interesting substance
son of different FQs with respect to OS is urgent for possible FQAD treatment.
to determine which FQs are safer in use and
(c) Supplementation of uni- and bivalent cations that are
which ones are more dangerous. Reduction of OS
chelated by FQs: the role of uni- and bivalent cations
is a very broad area. There are thousands of natu-
was partially discussed in point A. Additionally, the
ral substances which possess the antioxidant capac-
role of Mg2+ and K+ must be presented. Both ions
ity and which are able to reduce free radicals
possess high intracellular concentrations (Mg2+: 20x
leaked from ETC. One should, however, remember
and K+ 40x higher than extracellular). K+ is probably
that they work as one to one. It means that, as a
removed from the cell in the OS state by opening
rule, they are not reduced in the cell after free rad- redox-sensitive Kv1.5 channels. Mg2+ is strongly che-
ical annihilation in order to work in cycle. They lated by FQs, but, probably, it also escapes from the
only reduce the size of free radical damage. cells due to some unrecognized mechanisms. The
Among the antioxidants which enter easily, the mito- supplementation must take into consideration the
chondria are the most interesting ones. Lowes et al. [79] regulatory effect of kidney, which removes overdosed
show that the mitochondrion-targeted antioxidant MitoQ amounts of both cations to the urine. Thus, small but
protects against fluoroquinolone-induced oxidative stress often doses are rather recommended in order to keep
and mitochondrial membrane damage in human Achilles a bit higher concentrations of both ions in the blood
tendon cells. In cells treated with MitoQ, the oxidative plasma, which makes it possible to reduce the
stress was lower and mitochondrial membrane potential concentration gradients across the cell membranes
was maintained. and facilitate entering both to the cell.
Simonin et al. [97] report oxidative damage of collagen I (d) Supporting the mitochondrial replication in the
to be prevented by coadministration of N-acetylcysteine cell—pulling more damage to apoptosis and prolifer-
(150 mg/kg) to the mice. Tsai et al. report similar anticyto- ation of the more healthy ones: supporting the mito-
toxic effect of resveratrol [98]. Vitamins C and E belong also chondrial exchange (removing that destroyed ones
to this group; however, after they annihilate some radicals, and replication of that more healthy ones) is the nec-
they can be reduced using NADPH2. Some papers point to essary way in the case of irreversible mtDNA dam-
the ability of vitamin E to reduce the consequences of FQ- age. The substance that is postulated to possess the
induced damage [99]. Vitamin C is presented to possess the ability to promote the mitochondrial biogenesis is
ability to protect against lethal gamma photon irradiation pyrroloquinoline quinone (PQQ) [107, 108]. This
in mice—a strong source of OS [100]. Trace elements Zn2+, substance is also postulated to be OS protective [109].
Cu1/2+, Se2+, Fe2/3+, and Mn2+ are cofactors of important
antioxidative enzymes. Selenium supplementation is reported (e) Removing FQs permanently accumulated in the cells
[101] to partially restore oxidative stress and sperm damage in (if this phenomenon takes place): the problem of FQ
FQ-treated cells. accumulation is purely present in the available
Mn2+ seems to be very important, because it is a cofactor research. Thus, first, it is the urgent topic for estab-
of mitochondrial SOD2 being the first barrier against O2− lishing if this phenomenon really, and to what extent,
and carrying mtDNA against free radical damage. Thus, the takes place. Removing accumulated FQs may
amount of trace elements in the cell must be satisfactory. undergo in two ways: by cytochromes P-450 in the
Detailed research is required for Fe2/3+ and Cu1/2+ in order microsomes and by different processes which can
to find if their supplementation does not increase Fenton remove the molecule outside the cell. Activating the
reaction to occur. Citrate and other glycolysis inhibitors reduced cytochrome detoxification may be an impor-
may reduce the “hydrogen pressure” on ETC reducing to tant point in FQAD patients. On the other hand,
some degree LEC and OS. ozonation has been described to be an effective
method for removing the first generation FQ—flu-
(b) Restoring reduced mitochondrial potential ΔΨm: mequine from the liquid water [110]. Thus, ozone
restoring the reduced mitochondrial potential may therapy can be examined to be a method of FQ deg-
be one of the important steps in restoring the proper radation in the body.
regulatory balance in FQ-patients; however, it is not a
trivial task. On the one hand, reducing OS may con- (f) Regulating the disturbed epigenetics and enzyme
tribute to restoring ΔΨm; on the other hand, the rea- activities: every factor presented above contributes
sons of PTP opening seem to be more composed and to the disturbed gene expression which can contrib-
require advanced research. The points of interest ute to vicious circle-like regulations causing the new
may be reactivating HIF-1α system, reducing intra- regulatory balance lying far away from that optimal
cellular and intramitochondrial Ca2+ concentrations, one. If it is the main reason of the chronic state of
restoring membrane potential ΔV, and restoring FQAD patients, then there is a big chance to find
intracellular Mg2+, all contributing to PTP closing. methods for quick and effective treatment of this
Cyclosporine A and metformin are postulated to be state. However, the problem is of high complexity.
Conflicts of Interest [15] M. Dukewich, A. Danesh, C. Onyima, and A. Gupta, “Intrac-

table acute pain related to fluoroquinolone-induced periph-
The authors declare that there is no conflict of interest eral neuropathy,” Journal of Pain & Palliative Care
regarding the publication of this paper. Pharmacotherapy, vol. 31, no. 2, pp. 144–147, 2017.
[16] G. S. Tillotson, “Comment: peripheral neuropathy syndrome
and fluoroquinolones,” The Annals of Pharmacotherapy,
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Oxidative Medicine and Cellular Longevity

Krzysztof Michalak,1,2 Aleksandra Sobolewska-Włodarczyk,3 Marcin Włodarczyk,3

Correspondence should be addressed to Aleksandra Sobolewska-Włodarczyk; [email protected]

Received 1 July 2017; Accepted 20 August 2017; Published 25 September 2017

Academic Editor: Jacek Kurzepa

Norm OS (open PTP) Δ훹m

Unknown Tiredness + : Positive regulatory loops

O O Metal ion chelating seems to be the most fundamental

Conflicts of Interest [15] M. Dukewich, A. Danesh, C. Onyima, and A. Gupta, “Intrac-

The Scientific Gastroenterology Journal of

Journal of International Journal of

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