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Reactive
Oxygen
Species
April Luna, Mandy Luna, &
Tara Monroe
What is Reactive Oxygen Species?
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Reactive Oxygen Species or ROS is
defined as molecules or ions formed by the
incomplete one electron reduction of
oxygen
ROS are highly reactive due to unpaired
valence shell electrons
What is Reactive Oxygen Species?
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Reactive Oxygen Intermediates include:
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Singlet Oxygen
Superoxides
Peroxides
Hydroxyl Radical
Hypochlorous Acid
Where does ROS come from? What
does it do?
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Reactive Oxygen Species form as a natural
byproduct of the normal metabolism of oxygen
ROS is involved in:
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Microbial activity of Phagocytes
Regulation of signal transduction
Regulation of gene expression
Oxidative damage to nucleic acids, proteins, and lipids
What is the importance of ROS?
Bad vs. Good
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ROS – good
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plays a role in the induction of host defense
genes
Platelets involved in wound repair release ROS
to recruit additional platelets to an injury site
What is the importance of ROS?
Bad vs. Good
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ROS- bad
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Implicated in apoptosis, or programmed cell
death
Large amounts of ROS can cause DNA damage
in the cell which can lead to cancer
* Cells have a variety of defenses to protect
themselves from ROS, including two main
enzymes.
In the next slides, we will discuss:
- ROS and its involvement with antibiotics
- ROS and its involvement in cancer
- The different effects ROS has on humans
and mice
ROS in the presence of antibiotics…
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In an article discussing the action of
antibiotics it was found that the production
of ROS is a mechanism of cell death that is
induced by bactericidal antibiotics
In contrast, bacteriostatic antibiotics do not
cause ROS formation
ROS in the presence of antibiotics…
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Respiration in aerobic organisms results in the
formation of ROS which has been implicated in
the action of certain antibiotics.
It was also found that ROS is produced in E. coli
by the action of what is known as antibioticinduced mazEF-mediated cell death…
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mazEF mediates two cell death pathways, ROSdependent and ROS-independent.
How does ROS interact with
antibiotics?
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In some cases, ROS is produced as a
byproduct of antibiotic induced cell death in
bactericidal antibiotics
In an article discussing amoxicillin and
ROS it was found that Reactive Oxygen
Species cause amoxicillin to produce
oxidative damage of DNA in mammalian
cells
ROS and Amoxicillin
 Studies have shown that amoxicillin stimulates the ROS
at the same pace as the DNA lesion induction.
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ROS in mammalian cells cause the amoxicillin to
produce oxidative DNA damage. ROS increased
10 minutes after the intake of amoxicillin.
 ROS may help mediate several inflammatory
diseases, But if taken with amoxicillin, the ROS
increases thereby producing DNA damage.
The Connection between ROS and
DNA lesions
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DNA lesions are caused by damage to bases
during DNA synthesis. This damaged base often
causes disincorporation at the lesion site. These
mismatches have increased susceptibility to form
unpaired bases.
 Such DNA lesions are often caused by amoxicillin
leading to stimulation of the ROS at the same pace
as the DNA lesion induction.
What does ROS and Tetracycline HCl
do when put together?
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Tetracycline HCL is an antibiotic that is
often used in the treatment of acne
When used, it was found that this antibiotic
reduces/inhibits some ROS generation
from zymosan-stimulated
polymorphonuclear leukocytes (PMNL).
Erythromycin also inhibits ROS in the same
way
Do other antibiotics have the similar
effect on ROS?
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Some antibiotics such as erythromycin and
tetracycline HCL reduce ROS generation.
Cephalexin, penicillin G, streptomycin, and
chloramphenicol have no inhibitory effect
on ROS at tested concentrations
Therefore, certain antibiotics have the
ability to inhibit ROS generation by PMNL
while others do not
When are these antibiotics used and
for what?
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ROS-inhibiting antibiotics are used for:
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Resolving inflammatory acne lesions by acting
directly on PMNL as antioxidants
A combination of tetracycline HCL and ibuprofen
is an effective treatment for moderate acne
How does ROS
production and cancer link
together?
ROS and Cancer
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In a recent article researchers analyzed 10 human
prostate cancer microarray data sets. Researchers
determined:
 In the cell increased ROS level or decreased antioxidant
levels can lead to the ROS damaging lipids, proteins and
DNA
 Nrf2 and members of the glutathione-S-transferase family
decrease tremendously in the presence of ROS.
 DNA has extensive protection of cellular antioxidants
and detoxification enzymes. But even with these
protections, alterations occur causing cellular
transformation.
ROS and Cancer
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The loss of Nrf2 causes a decrease in GST expression and
increased levels of ROS. This ultimately leads to DNA
damage associated with tumorigenesis.
 (Erythroid 2p45 (NFE2) related factor 2 (Nrf2) is a basic
region leucine zipper transcription factor that
mediates gene expression through the antioxidant response ele
ment. )
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These studies suggest that if researchers can find a way
to maintain or enhance Nrf2 expression or activation, it
can lead to a new chemo-preventative strategy for
prostate cancer.
The different reaction ROS has on
human cells and mice
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In mice:
DNA and proteins are damaged by oxidation during tumor
progression.
There have been similar results in the transgenic
adenocarcinoma of the prostate, where increased oxidative
and nitrosative damage was shown in the prostate gland
during tumorigenisis.
– Expression of SV40 TAg and TAg antigens result in three
pocket proteins losing all functionality which directly
leads to prostate cancer.
The different reaction ROS has on
human cells and mice
 In humans:
 Nrf2 is down-regulated in prostate cancer
 The loss of Nrf2 results in reduced
expression and reduced activity of GST enzymes
which leads to increased ROS thereby increasing
DNA damage resulting in tumorigenisis.
Conclusion
ROS (Reactive Oxygen Species):
Chemical species that are formed upon
incomplete reduction of Oxygen and a
common mechanism of cell death
induced by bactericidal antibiotics.
Importance: Mediate the toxicity of
oxygen and also operate as intracellular
signaling. High levels of ROS has been
shown to increase DNA damage.
Conclusion
ROS and Antibiotic Interactions:
 Tetracycline HCL and Erythromycin inhibit some
of the ROS production by polymophonuclear
leukocytes (PMNL). In acne, the antibiotics used
for treatment reduce the ROS generation from
PMNL.
 Other antibiotics don’t have an inhibitory reaction
to ROS.
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Conclusion
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ROS and Amoxicillin: Amoxicillin stimulated the
ROS at the same pace as the DNA lesion
induction. ROS in mammalian cells cause the
amoxicillin to produce oxidative DNA damage.
ROS increased only after 10 minutes after the
intake of amoxicillin.
ROS may help mediate several inflammatory
diseases, but if taken with amoxicillin, the ROS
increases and produces DNA damage. It is good
and bad, depends on what antibiotic is taken.
Conclusion
ROS and cancer: High ROS levels have shown
to produce DNA damage and tumorigenesis.
 Nrf2(a basic-region leucine zipper transcription
factor) is activated by elevated ROS and is
currently being highly researched. The Nrf2 is
down regulated in prostate cancer and is
important for treatment. Decreased Nrf2 means
an elevated ROS and DNA damage.
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Conclusion
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ROS Future Research: ROS signaling and homeostasis and
their roles in aging is not currently known.
The biology and biochemistry of ROS is currently being
studied, but is hard because of the numerous cellular effects
it has.
The genetic description of the cellular and organism
mechanisms of ROS tolerance is needed.
The process ROS and antibiotics interactions and what
makes certain antibiotics inhibit or increase ROS levels.
The technique that ROS uses to damage DNA and increase
turmorigenesis.
References
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Kolodkin-Gal, I., Sat, B., and Kesh, A., and Engleberg-Kulka, H.
Dec. 2008.The communication factor EDF and the toxinantitoxin module mazEF determine the mode of antibiotics.
PLoS Biology 6:e319
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Miyachi, Y., Yoshioka, A, and Imamura, S., and Niwa, Y. 1986.Effect of
Antibiotics on the Generation of Reactive Species. Page 449-453.
Li, P., Chang, Y., and Tzang, B., and Chen, C., and Liu, Y. 2007.
Antibiotic amoxicillin induces DNA lesions in mammalian cells
possibly via reactive oxygen species. Mutation Research 629: 133-139.
Frohlich, D.D., McCabe, M.T., and Arnold, R.S., and Day, M.L.2008. The
role of Nrf2 in increased reactive oxygen species and DNA damage in
prostate tumorigenesis. Oncogene 27:4353-4362.
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Aurreauz, B.D. and Toledano, M.B. 2007. ROS as signaling
molecules: mechanisms that generate specificity in ROS
homeostasis. Nature Reviews 8: 813-824.
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