Return to Phototoxic Pesticides
Abstracts
KEYWORDS:
photocarcinogenic, photocarcinogenicity
photoclastogenic
photocytotoxic
photogenotoxic
photohemolytic
photomutagenic, photomutagenicity
phototoxic, phototoxicity
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Bay
Y3118
Ciprofloxacin
Clinafloxacin
Enoxacin
Fleroxacin |
Gemifloxacin
Grepafloxacin
Levofloxacin
Lomefloxacin |
Moxifloxacin
Norfloxacin
Ofloxacin
Pefloxacin
Sitafloxacin |
Sparfloxacin
Temafloxacin
Tosufloxacin
Trovafloxacin |
Name: |
Bay Y3118 |
CAS No. |
144194-96-7
|
Formula: |
C20-H21-Cl-F-N3-O3.Cl-H
|
Structure: |
|
Other Names: |
Bay
y 3118
Bay-Y3118 |
Class |
Fluoroquinolone |
Effects
(some, not all) |
•
Photogenotoxic
• Phototoxic
|
Use: |
na |
Bay
Y3118 Abstracts:
Recent reports on the
photochemical carcinogenicity and photochemical genotoxicity of
fluoroquinolone antibacterials led to an increasing awareness
for the need of a standard approach to test for photochemical
genotoxicity. In this study the micronucleus test using V79 cells
was adapted to photogenotoxicity testing. Results of using different
UVA/UVB relationships enabled us to identify a suitable irradiation
regimen for the activation of different kinds of photosensitizers.
Using this regimen, 8-methoxypsoralen and the
fluoroquinolones lomefloxacin, grepafloxacin and Bay Y 3118 were
identified to cause micronuclei and toxicity upon photochemical
activation.
Ref: The application of the micronucleus
test in Chinese hamster V79 cells to detect drug-induced photogenotoxicity;
by B Kersten et al. Mutat Res 1999 Sep 15;445(1):55-71.
...
After exposure to 10 and 30 mg Bay y 3118, a
dose-dependent induction of damage to the mtDNA was found,
whereas exposure to 3 and 1 mg showed no effect. NDEA (25 mg)
was used as positive control.
Ref: Damage to mitochondrial DNA induced by the quinolone Bay
y 3118 in embryonic turkey liver. By H Enzmann et al. Mutat Res
1999 Apr 6;425(2):213-24
Name: |
Ciprofloxacin |
CAS No. |
85721-33-1 |
Formula: |
C17-H18-F-N3-O3
|
Structure: |
|
Other Names: |
Too
many to list:
Commonly known as Cipro |
Class |
Fluoroquinolone
(Carboxyfluoroquinoline) |
Effects
(some, not all) |
•
Photogenotoxic
• Photohemolytic
• Potential to induce cartilage lesions in juvenile rats
• Chondrotoxicity
• Significantly
impaired both testicular function and structure in rats.
• Retarded
fracture healing in rats |
Use(s): |
Antibacterial
Anti-infective agent
A Carboxyfluoroquinoline
antimicrobial agent that is effective against a wide range
of microorganisms. It has been successfully and safely used
in the treatment of resistant respiratory, skin, bone, joint,
gastrointestinal, urinary, and genital infections. |
Ciprofloxacin
Abstracts:
AIM:
To compare two methods of measuring DNA damage induced by photogenotoxicity
of fluoroquinolones (FQ).
METHODS: Lomefloxacin (LFLX), sparfloxacin (SPFX), ciprofloxacin
(CPFX), and levofloxacin
(LELX) were tested by comet assay and photodynamic DNA strand
breaking activity under the different conditions of UVA irradiation.
RESULTS: In comet assay, photogenotoxicity
was evident at SPFX 1 mg/L,
LFLX 5 mg/L, and CPFX
5 mg/L, and LELX 10 mg/L. In photodynamic DNA strand-breaking
activity, SPFX and LFLX induced the conversion of the supercoiled
form into the nicked relaxed form at 10-50 micromol/L, while CPFX
at 25 micromol/L and LELX at 50 micromol/L.
CONCLUSION: There were good correlations between the two methods
to detect DNA damage induced by phototoxicity of fluoroquinolones.
Photodynamic DNA strand breaking activity was a good method to
detect DNA damage induced by photogenotoxicity
of fluoroquinolones as well as comet assay.
Ref: Compare two methods of measuring DNA
damage induced by photogenotoxicity of fluoroquinolones. By Zhang
T, Li JL, Xin J, Ma XC, Tu ZH. Acta Pharmacol Sin. 2004 Feb;25(2):171-5.
Ofloxacin
and ciprofloxacin are two closely-related fluoroquinolones which
both induce chondrotoxicity in juvenile dogs.
In immature rats, however, cartilage lesions have been described
with ofloxacin only...We conclude that ciprofloxacin
an N-Methyl-ciprofloxacin - as other fluoroquinolines - have the
potential to induce cartilage lesions in juvenile rats.
Ref: Ciprofloxacin and N-methyl-ciprofloxacin
induce joint cartilage lesions in immature rats. By E Lozo et
al. Teratology 1996 May;53(5):32A.
The phototoxic potential
of eight fluoroquinolones (norfloxacin, ofloxacin, enoxacin, ciprofloxacin,
lomefloxacin, tosufloxacin, sparfloxacin
and gatifloxacin) was evaluated by using three in vitro methods
of cytotoxicity against mammalian cells, erythrocyte lysis and
DNA strand breakage. All fluoroquinolones
tested with the exception of gatifloxacin, an 8-methoxy quinolone,
showed DNA strand breaking activities under UV-A irradiation.
Their cytotoxicity against HeLa cells was also enhanced by UV-A
irradiation. In particular, the phototoxic
potential of sparfloxacin, enoxacin and lomefloxacin was high
in both methods. Ofloxacin is very photocytotoxic against
HeLa cells, while it has low potential to cause DNA strand breakage.
Norfloxacin, ciprofloxacin and enoxacin
were very photohemolytic, but sparfloxacin was not, indicating
that the in vivo phototoxic potencies of fluoroquinolones might
not be predictable by the photohemolysis study. Gatifloxacin,
a non-phototoxic quinolone, showed no phototoxic potential in
any of these three in vitro tests. These results suggest that
determination of DNA strand breaking activity, combined with cytotoxicity
against mammalian cells, is available to predict the phototoxic
potential of fluoroquinolones without laboratory animals.
Ref: In vitro method for prediction of the
phototoxic potentials of fluoroquinolones; by T. Yamamoto et al.
Toxicology in Vitro - Volume 15, Issue 6 , December 2001, Pages
721-727.
In the last few years,
a marked decrease in male fertility has been reported. Environmental
factors were recently suspected for this effect. Among those factors
is the misuse of drugs and in particular antibiotics. Quinolones
are a group of antibacterial agents with broad-spectrum activity.
Testicular impairment of some quinolone members is controversial;
a matter which stimulated our attention to investigate the adverse
testicular effects of the most familiar quinolone members, namely:
ofloxacin, ciprofloxacin and pefloxacin. They were given to rats
in doses of 72, 135 and 72 mg kg-1day-1p.o., respectively, for
15 consecutive days. Ofloxacin was also used to establish a dose–response
relationship in doses of 36, 72 and 360 mg kg-1day-1p.o. for 15
consecutive days. Results revealed that
ofloxacin, ciprofloxacin and pefloxacin reduced testicular LDH-X
activity by 39.8%, 62.7% and 60.7%, respectively. Moreover, sperm
count, motility and daily sperm production were markedly decreased.
Ofloxacin induced a dose-dependent decrease in testicular LDH-X
activity, sperm count and motility. Furthermore, daily sperm production
showed a marked reduction which amounted to 26.1% and 40.0% following
administration of ofloxacin (72, 360 mg kg-1day-1*15 days), respectively.
Moreover, administration of ofloxacin resulted in marked testicular
histopathological changes. It is concluded that, ofloxacin, ciprofloxacin
and pefloxacin significantly impaired both testicular function
and structure in rats.
Ref: ADVERSE TESTICULAR EFFECTS OF SOME
QUINOLONE MEMBERS IN RATS; by ADEL R. A. ABD-ALLAH et al. Pharmacological
Research Volume 41, Issue 2 , February 2000, Pages 211-219.
BACKGROUND: The objective
of the present study was to test and compare the effect of floroquinolones
on fracture healing as assessed histopathologically. METHODS:
A total of twenty five Wistar rats were arbitrarily assigned to
five groups with five animals each. Bilateral closed femoral fracture
was constructed manually in all groups. The first group did not
receive any drug as control (C). The 2nd, 3rd, 4th, and the last
group were treated with norfloxacin (N),
ofloxacin (O), pefloxacin (P) and ciprofloxacin (Ci) respectively.
Antibiotic administration was started on the 7th day after the
fracture incident. All the treatments were discontinued twenty
days after the incident all the rats were sacrificed , and the
fracture calluses together with affected femurs were resected
en bloc at the fourth week after fracture. RESULTS: Average healing
grades of control group was higher than all the other antibiotic
groups. Mean healing grades of control ( 5 ; n:8), ofloxacin (4.1;
n:7), ciprofloxacin (3.9; n:8), norfloxacin (3.4 ; n:9) and pefloxacin
groups (2.6 ; n:10) were recorded.. Statistically significant
differences between antibiotherapy groups ( excluding. norfloxacin)
and the control group were detected. CONCLUSIONS: The current
histopathological study has shown that all
the studied floroquinolones retarded fracture healing in rats.
Ref: A Comparison of effects of floroquinolones
on fracture healing (An experimental study in rats). By Tuncay
I, Ozbek H, Kosem M, Unal O. Ulus Travma Derg. 2005 Jan;11(1):17-22.
Name: |
Clinafloxacin |
CAS No. |
105956-97-6
|
Formula: |
C17-H17-Cl-F-N3-O3
|
Structure: |
|
Other Names: |
PD 127321
|
Class |
Fluoroquinolone |
Effects
(some, not all) |
• Photoclastogenic
• Photogenotoxic
• Phototoxic
• Hypoglycaemia |
Use(s): |
Antiinfective
agent |
Clinafloxacin
Abstracts:
... Phototoxicity has
been described for all quinolones, but derivatives
with a halogen atom at position 8 show the highest potential for
such reactions (e.g. clinafloxacin)...
Ref: Clinical toxicological aspects of fluoroquinolones;
by Ralf Stahlmann. Toxicology Letters - Volume 127, Issues 1-3
, 28 February 2002, Pages 269-277.
The photochemical clastogenic
potential of 12 quinolone antibacterial agents with or without
light irradiation was assessed by an in vitro chromosomal aberration
test using cultured CHL cells. Exposure to all test compounds,
except for DK-507k, increased the incidence of cells with structural
aberrations excluding gap (TA) following light irradiation. Test
compounds used in the present study under light irradiation were
divided into three groups based on their ED50 values, doses inducing
chromosomal aberrations in 50% of cells. The
first group with ED50 values below 30 g/ml includes sparfloxacin
(SPFX), clinafloxacin (CLFX), gemifloxacin
(GMFX), lomefloxacin (LFLX), sitafloxacin (STFX), grepafloxacin
(GPFX) and fleroxacin (FLRX); the second group with ED50 values
of 100 g/ml, enoxacin (ENX) and levofloxacin (LVFX);
the third group with little or no potency, moxifloxacin (MFLX),
trovafloxacin (TVFX) and DK-507k. The photochemical
clastogenicity of these compounds correlates well with their reported
in vivo phototoxic potentials. In
the chemical structure and clastogenicity relationships, substitution
of a methoxy group at the C-8 position in the quinolone nucleus
was confirmed to reduce not only photochemical clastogenicity,
but also the clastogenic potential of quinolone antibacterial
agents.
Ref: In vitro photochemical clastogenicity
of quinolone antibacterial agents studied by a chromosomal aberration
test with light irradiation. By Satoru Itoh et al. Mutation Research/Genetic
Toxicology and Environmental Mutagenesis Volume 517, Issues 1-2
, 27 May 2002, Pages 113-121.
Fluoroquinolone antiinfective drugs exhibit phototoxic, photogenotoxic,
and photocarcinogenic activities in experimental systems which
may be interrelated. Clinafloxacin (CLX), a new fluoroquinolone,
is a potent antiinfective agent being developed for use in life-threatening
infections. While this drug has previously been demonstrated to
be phototoxic, this report evaluated the photogenotoxic and photocarcinogenic
potential of CLX. When Skh-1 mice were administered CLX in the
presence of ultraviolet light (UVA) at the maximum tolerated dose
expected for a photocarcinogenicity bioassay, induction of DNA
strand breakage was noted in keratinocytes isolated from these
animals. When compared with other well-studied fluoroquinolonesin
vitro,CLX and Lomefloxacin (LMX) were equally effective in producing
chromosome damage and DNA strand breakage in Chinese hamster ovary
(CHO) cells exposed to UVA. Treatment of CHO cells with CLX in
the presence of UVA also resulted in hydroxyl radical formation.
However, coincubation of CHO cells with CLX and various antioxidants
markedly reduced hydroxyl radical formation, but inhibited photogenotoxicity
only to a limited extent. Thus, while reactive oxygen species
contribute to the photogenotoxic activity of CLX, other factors
may be involved. Since CLX exhibits both
phototoxic and photogenotoxic activity, we predict that CLX would
be photocarcinogenic in vivo.The present study
suggests that under conditions of human exposure, the potential
risk for CLX-induced photocarcinogenicity is small.
Ref: In VitroPhotogenotoxic Activity of
Clinafloxacin: A Paradigm Predicting Photocarcinogenicity; by
S. J. Bulera1, J. C. Theiss, T. A. Festerling and F. A. de la
Iglesia. Toxicology and Applied Pharmacology Volume 156, Issue
3 , 1 May 1999, Pages 222-230.
The new fluoroquinolones (clinafloxacin, gatifloxacin, gemifloxacin,
grepafloxacin, levofloxacin, moxifloxacin, sitafloxacin, sparfloxacin
and trovafloxacin) offer excellent activity against Gram-negative
bacilli and improved Gram-positive activity (e.g. against Streptococcus
pneumoniae and Staphylococcus aureus) over ciprofloxacin... Several
of these agents have either been withdrawn from the market, had
their use severely restricted because of adverse effects (clinafloxacin
because of phototoxicity and hypoglycaemia; grepafloxacin
because of prolongation of the QTc and resultant torsades de pointes;
sparfloxacin because of phototoxicity; and trovafloxacin
because of hepatotoxicity), or were discontinued during developmental
phases. The remaining fluoroquinolones such as gatifloxacin, gemifloxacin,
levofloxacin and moxifloxacin have adverse effect profiles similar
to ciprofloxacin. Extensive post-marketing safety surveillance
data (as are available with ciprofloxacin and levofloxacin) are
required for all new fluoroquinolones before safety can be definitively
established. Drug interactions are limited; however, all fluoroquinolones
interact with metal ion containing drugs (eg. antacids)..
Ref: A critical review of the fluoroquinolones:
focus on respiratory infections; by GG Zhanel et al. Drugs. 2002;62(1):13-59.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11790155
Name: |
Enoxacin |
CAS No. |
74011-58-8
|
Formula: |
C15-H17-F-N4-O3
|
Structure: |
|
Other Names: |
AT-2266
BRN 3628995
Bactidan
CCRIS 5242
CI 919
Comprecin
Enoram
Flumark
PD 107779
Penetrex |
Class |
Fluoroquinolone |
Effects
(some, not all) |
•
Photogenotoxic
• Photoclastogenic
•
Photohemolytic •
Phototoxic |
Use: |
An orally
administered broad-spectrum fluoroquinolone antibacterial agent
active against most gram-negative and gram-positive bacteria.
Its clinical efficacy has been confirmed in a variety of systemic
infections and particularly in urinary tract infections. The
drug is well tolerated by adults, but should not be used in
children and pregnant women. |
Enoxacin
Abstracts:
The phototoxic potential
of eight fluoroquinolones (norfloxacin, ofloxacin, enoxacin,
ciprofloxacin, lomefloxacin, tosufloxacin,
sparfloxacin and gatifloxacin) was evaluated by using three
in vitro methods of cytotoxicity against mammalian cells, erythrocyte
lysis and DNA strand breakage. All fluoroquinolones
tested with the exception of gatifloxacin, an 8-methoxy quinolone,
showed DNA strand breaking activities under UV-A irradiation.
Their cytotoxicity against HeLa cells was also enhanced by UV-A
irradiation. In particular, the phototoxic
potential of sparfloxacin, enoxacin and lomefloxacin was high
in both methods. Ofloxacin is very photocytotoxic against
HeLa cells, while it has low potential to cause DNA strand breakage.
Norfloxacin, ciprofloxacin and enoxacin
were very photohemolytic, but sparfloxacin was not, indicating
that the in vivo phototoxic potencies of fluoroquinolones might
not be predictable by the photohemolysis study. Gatifloxacin,
a non-phototoxic quinolone, showed no phototoxic potential in
any of these three in vitro tests. These results suggest that
determination of DNA strand breaking activity, combined with cytotoxicity
against mammalian cells, is available to predict the phototoxic
potential of fluoroquinolones without laboratory animals.
Ref: In vitro method for prediction of the
phototoxic potentials of fluoroquinolones; by T. Yamamoto et al.
Toxicology in Vitro - Volume 15, Issue 6 , December 2001, Pages
721-727.
The photochemical clastogenic
potential of 12 quinolone antibacterial agents with or without
light irradiation was assessed by an in vitro chromosomal aberration
test using cultured CHL cells. Exposure to all test compounds,
except for DK-507k, increased the incidence of cells with structural
aberrations excluding gap (TA) following light irradiation. Test
compounds used in the present study under light irradiation were
divided into three groups based on their ED50 values, doses inducing
chromosomal aberrations in 50% of cells. The
first group with ED50 values below 30 g/ml includes sparfloxacin
(SPFX), clinafloxacin (CLFX), gemifloxacin (GMFX), lomefloxacin
(LFLX), sitafloxacin (STFX), grepafloxacin (GPFX) and fleroxacin
(FLRX); the second group with ED50 values of 100 g/ml, enoxacin
(ENX) and levofloxacin (LVFX); the third group with little
or no potency, moxifloxacin (MFLX), trovafloxacin (TVFX) and DK-507k.
The photochemical clastogenicity of these
compounds correlates well with their reported in vivo phototoxic
potentials. In the chemical structure
and clastogenicity relationships, substitution of a methoxy group
at the C-8 position in the quinolone nucleus was confirmed to
reduce not only photochemical clastogenicity, but also the clastogenic
potential of quinolone antibacterial agents.
Ref: In vitro photochemical clastogenicity
of quinolone antibacterial agents studied by a chromosomal aberration
test with light irradiation. By Satoru Itoh et al. Mutation Research/Genetic
Toxicology and Environmental Mutagenesis Volume 517, Issues 1-2
, 27 May 2002, Pages 113-121.
Name: |
Fleroxacin |
CAS No. |
79660-72-3 |
Formula: |
C17-H18-F3-N3-O3
|
Structure: |
|
Other Names: |
AM 833
BRN 4300996
CCRIS 3972
Megalone
Ro 23-6240
Ro 23-6240/000 |
Class |
Fluoroquinolone |
Effects
(some, not all) |
•
Photocarcinogenic
•
Photoclastogenic •
Phototoxic |
Use: |
Anti-infective
agents, fluoroquinolone
Antibacterial
Drug / Therapeutic Agent
6,8-Difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic
acid. A third-generation fluoroquinolone derivative with a
broad antimicrobial spectrum. The drug strongly inhibits the
DNA-supercoiling activity of DNA gyrase which may account
for its antibacterial activity. |
Fleroxacin
Abstracts:
...
Fluoroquinolones (FQ)
are a relatively new class of antibacterials that are useful in
the treatment of gram-negative bacterial infections. When
used in humans FQ's often cause phototoxicity.
Recent studies have shown that lomefloxacin and fleroxacin cause
squamous cell carcinomas in hairless mice injected
with these drugs and irradiated with UV-A (315-400) nm. We have
studied the photochemical properties of lomefloxacin and related
FQ's to determine why these drugs as a class are phototoxic and
why lomefloxacin and fleroxacin are photocarcinogenic.
Singlet oxygen (1O2) and superoxide yields for the FQ antimicrobials
do not correlate with their phototoxic potentials. However, photocleavage
of pBR322 DNA by the FQ antibiotics is at least 10-fold more efficient
for difluorinated quinolones (lomefloxcin and fleroxacin) than
for monofluorinated analogs. 1O2 does not induce photocleavage.
Futhermore, the inhibitory effect of O2 on the induction of frank
strand breaks makes it unlikely that superoxide could play a major
role in the photocleavage of DNA by these antibiotics.
We have now found that upon UVA-irradiation the F-8 fluorine atoms
of lomefloxacin and fleroxacin are lost as fluoride with the concomitant
generation of a carbene at C-8. In contrast
non-photocarcinogenic FLQ's norfloxacin and ciprofloxacin did
not exhibit UVA-induced fluoride loss...
Ref: MECHANISMS
OF CHEMICALLY INDUCED PHOTOSENSITIVITY by CF CHIGNELL. 1997
- Crisp Data Base National Institutes of Health. Document Number:
CRISP/98/ES50046-19.
The photochemical
clastogenic potential of 12 quinolone antibacterial agents with
or without light irradiation was assessed by an in vitro chromosomal
aberration test using cultured CHL cells. Exposure to all test
compounds, except for DK-507k, increased the incidence of cells
with structural aberrations excluding gap (TA) following light
irradiation. Test compounds used in the present study under light
irradiation were divided into three groups based on their ED50
values, doses inducing chromosomal aberrations in 50% of cells.
The first group with ED50 values below 30 g/ml
includes sparfloxacin (SPFX), clinafloxacin (CLFX), gemifloxacin
(GMFX), lomefloxacin (LFLX), sitafloxacin
(STFX), grepafloxacin (GPFX) and fleroxacin
(FLRX); the second group with ED50 values of 100 g/ml, enoxacin
(ENX) and levofloxacin (LVFX); the third group with little
or no potency, moxifloxacin (MFLX), trovafloxacin (TVFX) and DK-507k.
The photochemical clastogenicity of these
compounds correlates well with their reported in vivo phototoxic
potentials. In the chemical structure
and clastogenicity relationships, substitution of a methoxy group
at the C-8 position in the quinolone nucleus was confirmed to
reduce not only photochemical clastogenicity, but also the clastogenic
potential of quinolone antibacterial agents.
Ref: In vitro photochemical clastogenicity
of quinolone antibacterial agents studied by a chromosomal aberration
test with light irradiation. By Satoru Itoh et al. Mutation Research/Genetic
Toxicology and Environmental Mutagenesis Volume 517, Issues 1-2
, 27 May 2002, Pages 113-121.
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