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What Oxidant Compounds Are Useful Medicinally ?
By What Mechanism(s) Do They Function As Medicinal Oxidants?
~~~ LISTS OF CLINICALLY USEFUL OXIDANTS ~~~
hyperbaric oxygen (O2), singlet oxygen (O2),
ozone (O3), hydrogen peroxide (H2O2),
magnesium peroxide (MgO2), zinc peroxide (ZnO2),
chlorine dioxide (ClO2), chlorite (ClO2-),
nitrate (NO3-), permanganate (MnO4-), iodine (I2)
organic ozonides (RO3R'), organic peroxides (ROOR'),
quinones (Q), alphaketoaldehydes (RCOCHO),
imidazoles, methylene blue
disulfides (RSSR'), sulfoxides (RSOR'),
disulfide monoxides (RSSOR')
~~~ INORGANIC PEROXIDES ~~~
Hydrogen peroxide (H2O2)
Magnesium peroxide (MgO2)
Zinc peroxide (ZnO2)
Peroxides of cationic metals yeild hydrogen peroxide
upon neutral or acid hydrolysis.
XO2 + 2H+ ---> X++ + H2O2
Three main mechanisms exist whereby H2O2
may deplete hydrogen from available carriers.
1. glutathione peroxidase system
2. mitochondrial cytochromes
3. nonspecific peroxidases
~~~ GLUTATHIONE PEROXIDASE SYSTEM ~~~
This BETS starts with sugar as the original [H] donor
and ends with HOOH or LOOH as the final [H] acceptor.
G6P ... NADP+/NADPH ... FAD/FADH2 ...
GSSG/GSH ... cys-Se/cys-SeH ... LOOH/LOH+HOH
Note that when all components are present,
this BETS can function as an efficient depletor
of reductants from the NADPH and GSH pools.
Sugars, NADPH, or GSH might otherwise be useful for
syntheses and support the proliferation of pathogens.
Blockade by cysteine deficiency, by selenium deficiency,
or by mercury toxicity inhibit the function of this BETS.
~~~ RESPIRATORY CYTOCHROMES AS ACTIVATORS OF H2O2 ~~~
The cytochromes are ferroporphyrin containing proteins
which sequentially carry electrons in the mitochondria.
Cytochrome a3 contains both iron and copper cations and
is activated by diatomic oxygen or by hydrogen peroxide.
The respiratory electron transport chain
can be abbreviated as follows:
Krebs Cycle ... NAD+/NADH ... FMN/FMNH2 ... CoQ/CoQH2
... cytB-Fe+++/cytB-Fe++ ... cytC-Fe+++/cytC-Fe++
... cytA-Cu++/cytA-Cu+ ... O2/HOH or HOOH/HOH
O2 or H2O2 activate cytosol to mitochondrial shuttles:
NADH ... DHAP/G3P ... FAD/FADH2 ... CoQ/CoQH2 ...
~~~ AUTOREGENERATION OF HYDROGEN PEROXIDE ~~~
1) Hydrogen peroxide attaches to the active center
HOOH + P ---> P**
2) One hydrogen atom is abstracted from a divalent
2HXH + P** ---> 2(HX*) + P + 2HOH
3) The radicalized donors are oxidatively quenched
by diatomic oxygen.
2(HX*) + 2OO ---> 2X + 2(-OO*) + 2H+
4) Superoxide is dismutated or reduced.
2(-OO*) + 2H+ ---> OO + HOOH
(-OO*) + AOH + H+ ---> AO* + HOOH
The HOOH produced in 4) can restart
the process as in 1) repeatedly.
By cancelling out all substances which appear
on both sides of these equations, the overall
effect is shown below.
2HXH + OO ---> 2X + 2HOH
According to this composite equation the overall
effect is to dehydrogenate large quantities
of divalent reductants.
A non-mitochondrial consumption of one molecule
of diatomic oxygen occurs with each cycle.
Thus low dose administration of HOOH can have
a profound oxidative impact by this mechanism.
~~~ ALDEHYDE REACTIONS ~~~
Aldehydes can reversibly add to thiols and to amines and
therefore be stored or carried covertly and indefinitely.
R--C==O + R'--SH <---> R--C--OH
H H H
R--C==O + R'--NH2 <---> R--C--OH <---> R--C==NR' + H2O
In the hydrated form aldehydes are dehydrogenated
by aldehyde oxidases.
R--C==O + HOH ---> R--C--OH - 2 [H] ---> R--C==O
~~~ ALDEHYDES AS PRO-OXIDANTS ~~~
Aldehyde oxidases catalyze the following reaction:
RCHO + H2O + 2 O2 ---> RCOOH + 2 -OO* + 2 H+
Their mechanism can be represented by the following BETS:
RCOOH/RCHO ... Mo(+6)/Mo(+5) ... FAD/FADH* ...
Fe(+3)/Fe(+2) ... O2/-OO*
The superoxide produced can be dismutated:
-OO* + -OO* + 2 H+ ---> O2 + HOOH
The superoxide can also be reduced by ambient antioxidants:
-OO* + H+ ---> HOO*
HOO* + AOH ---> AO* + HOOH
Note that in either case hydrogen peroxide is produced.
Thus superoxide, hydroperoxyl radical, and hydrogen peroxide
are produced when aldehyde are oxidized.
These oxidants would consume [H] and:
1) at very low doses might activate the immune system,
2) at low doses inhibit the growth of pathogens,
3) at higher doses cause oxidative damage.
~~~ FORMATION AND HYDROLYSIS OF OZONIDES ~~~
/O\ O O O-O
O O O || / \
OOO + R-C==C-R' --> R-C---C-R'--> R-C + C-R'--> R-C C-R'
H H H H H H H \O/ H
O O OH O H O
O || O || O ||
HOH + R-C + C-R' --> R-C-OH + C-R' --> R-C=O + O + C-R'
H H H H H H H
O-O + HOH OH OH O H O
/ \ O OH O || O ||
R-C C-R' --> R-C-O-C-R'--> R-C-OH + C-R'--> R-C=O + O + C-R'
H \O/ H H H H H H H H
Note that upon hydrolysis by either mechanism,
for each molecule of ozonide present there is produced:
one molecule of hydrogen peroxide plus two aldehydes.
~~~ ORGANIC HYDROPEROXIDES AS HYDROGEN ACCEPTORS ~~~
Organic hydroperoxides (ROOH) can consume reducing
equivalents along the glutathione peroxidase BETS.
G6P ... NADP+/NADPH ... FAD/FADH2 ...
GSSG/GSH ... cys-Se/cys-SeH ... ROOH/ROH+HOH
Polyunsaturated fatty acids which have undergone
lipid peroxidation can activate this sequence.
Also the "ene reaction" of PUFA's with singlet oxygen
produces lipid hydroperoxides.
In research certain organic hydroperoxides are often
used as oxidant probes, namely:
- tertiary butyl hydroperoxide
- cumene hydroperoxide
- benzoyl peroxide
~~~ OXIDES OF CHLORINE ~~~
1) The element chlorine can occur in various
oxides and valences as follows:
Cl2 Cl- ClO- ClO2- ClO2 ClO3- ClO4-
2) The chloride oxides can release one atom of oxygen
which strongly abstracts two hydrogen atoms
from numerous donors:
XH2 + ClO- ---> X + Cl- + H2O
3) The chlorine oxides are so strong they can
turn hydrogen peroxide into singlet oxygen:
HOOH + ClO- ---> O==O + Cl- + H2O
4) Myeloperoxidase physiologically produces
hypochlorite from hydrogen peroxide:
HOOH + Cl- ---> ClO- + HOH
5) Electrolysis of saline produces hypochlorite:
cathode: 2 e- + 2 H2O ---> H2 + 2 OH-
anode: 2 Cl- - 2 e- ---> Cl2
Cl2 + 2 OH- ---> Cl- + ClO- + H2O
6) Chlorite in acid solution produces chlorine dioxide:
4 HClO2 ---> 2 ClO2 + ClO3- + Cl- + 2H+ + H2O
7) Chlorine dioxide in alkaline solution produces:
2 ClO2 + 2 OH- ---> ClO2- + ClO3- + H2O
~~~ SULFUR COMPOUNDS AS WEAK OXIDANTS ~~~
S8 + 16 GSH ---> 8 H2S + 8 GSSG
ORGANIC DISULFIDES (e.g. products of other oxidants):
RSSR + 2 GSH ---> 2 R-SH + GSSG
DIALKYL SULFOXIDES (e.g. DMSO):
RSR + 2 GSH ---> RSR + H2O + GSSG
DISULFIDE MONOXIDES (e.g. allicin):
RSSR + 4 GSH ---> 2 RSH + H2O + 2 GSSG
~~~ ANODIC OXIDATION AS THERAPY ~~~
Electrolysis using direct current has been studied
for its growth stimulating and antitumor effects.
One of the most interesting applications of this
has been the work of Bjorn E. W. Nordenstrom, 1983,
"Biologically Closed Electric Circuits",pp 269-317
Using precisely calibrated direct current applied
to silver electrodes surgically placed within tumors,
regressions are readily and repeatably produced.
As expected from bioelectronic theory,
the positively charged electron collecting anode
is the pole applied to the tumors.
Four theories can be advanced to explain this:
1) anodic oxidation of electron/hydrogen carriers
2) electrolysis of water producing acid (H+)
3) release of focally toxic silver cation (Ag+)
4) conversion of chloride (Cl-) to chlorine (Cl2)
~~~ ELECTROLYSIS OF TISSUE ~~~
+ | | | -
| | | | |
+ + + + - - - -
2RSH - 2e -> RSSR + 2H+ RSSR + 2e + 2H+ -> 2RSH
_ _ _
2H2O - 4e -> O2 + 4H+ 2H2O + 2e -> H2 + 2OH
Ag - e -> Ag+
2Cl - 2e -> Cl2