Volume 04 Issue 10-2024
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American Journal Of Applied Science And Technology
(ISSN
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VOLUME
04
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Pages:
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ABSTRACT
As a result of the development of industrial technologies and changes in the ecological environment, various
xenobiotics released into the environment are increasing. Increasing exposure to xenobiotics may lead to the
development of diseases associated with toxic hepatitis (TG) in the population. The following exogenous factors can
cause TG: industrial and household toxic substances, chlorinated hydrocarbons, naphthalene and biphenyls, benzene,
metals and other inorganic elements, monomers used for the production of polymer materials, plastics, hydrazine and
its derivatives, as well as dioxins and radionuclides. All of these exogenous toxins have a cumulative damaging effect
on the liver, so they must be converted into non-toxic compounds for the div and eliminated. The main mechanisms
of toxic damage to the liver are lipid peroxidation, protein denaturation, reduction of ATF, mitochondrial dysfunction,
inhibition of membrane receptors.
KEYWORDS
Hepatitis, hepatotoxic, metabolism, tetrachloromethane, mitochondria, mPTP.
INTRODUCTION
The liver plays a major role in every stage of
metabolism and, together with other systems, is
responsible for the adequate response of the div to
external and internal changes. Today, despite the
success achieved in the prevention and treatment of
many diseases, the incidence and mortality rate of liver
Research Article
THE EFFECT OF POLYPHENOL COMPOUNDS ON Ca2+-INDUCED
MITOCHONDRIAL POTORAGE (mPTP) IN TOXIC HEPATITIS
Submission Date:
October 20, 2024,
Accepted Date:
October 25, 2024,
Published Date:
October 30, 2024
Crossref doi:
https://doi.org/10.37547/ajast/Volume04Issue10-20
Mallayeva Mavjudakhon Makhramovna
Samarkand State Medical University, Samarkand. Uzbekistan
Jizzakh branch of the National University of Uzbekistan, Jizzakh. Uzbekistan
Mustafakulov Mukhammadjon Abduvaliyevich
Samarkand State Medical University, Samarkand. Uzbekistan
Journal
Website:
https://theusajournals.
com/index.php/ajast
Copyright:
Original
content from this work
may be used under the
terms of the creative
commons
attributes
4.0 licence.
Volume 04 Issue 10-2024
127
American Journal Of Applied Science And Technology
(ISSN
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2771-2745)
VOLUME
04
ISSUE
10
Pages:
126-135
OCLC
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Publisher:
Oscar Publishing Services
Servi
diseases shows a steady growth trend. Due to the
increased exposure to environmental factors, the
increasing amount of industrial and chemical synthesis
products, hepatoprotectors, which increase the
resistance of the liver to the effects of chemicals and
normalize the functions of the response to toxic stress,
are becoming increasingly important [1-2 ].
Hepatotoxicants have different mechanisms of action,
depending on which group they belong to. In general,
their harmful effect consists of changing the
membrane and enzyme apparatus of hepatocytes due
to increased oxidation of lipids, as well as the
accumulation of toxic metabolites - hepatotoxin
biotransformation products. Therefore, in the case of
toxic damage to the liver, first of all, antioxidant
therapy is used, which limits the factors affecting the
functional state of liver cell membranes and ensures
their histological integrity [3-5].
The purpose of the subject
Study of the effect of polyphenolic compounds on
Ca2+-induced mitochondrial permeability transition
(mPTP) in toxic hepatitis.
METHODS
Tetrachloromethane (CCl4) solution in 50% olive oil was
challenged by parenteral administration twice at a
dose of 2 ml/kg in 1 day [12]. Medicines Slymarin
(pharmacological sales name Karsil) 50 mg/kg, sumax
10 mg/kg, glabra 10 mg/kg were administered orally
within 7 days after hepatitis was induced in a dose of 10
mg/kg. Extraction of liver tissue homogenate We
isolated 150-200 grams of rat liver tissue homogenate
by differential centrifugation. Blood was collected
from the animals, centrifuged at 3000 rpm for 12
minutes, serum was separated and biochemical
indicators were studied. Alanine aminotransferase
activity in serum was determined by the single
Reitman-Frenkel method [6].
RESULTS
Mitochondria are the major cellular organelles that
produce almost 95% of the ATF used in mammalian cells
through oxidative phosphorylation. Mitochondria also
play an important role in homeostasis of calcium ions.
when the cytosolic Ca2+ concentration exceeds a
threshold, mitochondria can rapidly accumulate Ca2+
and release it slowly. Regardless of its participation in
oxidative phosphorylation, Ca2+ in mitochondria also
participates in cytosolic calcium signals and activates
the mitochondrial apoptosis mechanism by inducing
mPTP opening in the mitochondrial inner membrane. It
is widely recognized that abnormal elevations of
intracellular
Ca2+
can
induce
mitochondrial
strangulation by opening the mPTP [12, 22]. The action
of prooxidant factors can cause the active opening of
mitochondrial mPTP, and as a result, swelling can
occur. Opening of the mitochondrial mPTP prolonged
pore allows the rapid passage of ions and large
molecules, which can lead to cell death. CCl4 is a toxic
compound
and
has
pro-oxidant
properties.
Administration of CCl4 to rats not only increases blood
ALT, AST, and alkaline phosphatase enzymes, but also
disrupts the exchange of calcium ions in liver cells,
including mitochondria. Violation of Ca2+ retention
property of mitochondria occurs in pathophysiological
processes associated with energy limitation and even
hepatoprotective diseases [13, 25,].
In conditions of toxic hepatitis, the destruction of
mitochondria can be inhibited by bioactive substances
extracted from plants. The effect of selected glabra,
summax polyphenols for the study on the Ca2+ ion-
induced swelling of rat liver mitochondria under toxic
heapatitis conditions was studied in comparative in
vivo experiments with the flavonoid quercetin [11, 15-
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VOLUME
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OCLC
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19]. A very important morphological sign of
mitochondrial damage is their swelling. Swelling of
mitochondria is observed, for example, in myocardial
cells in heart failure, in hepatitis, as well as in many
infectious, hypoxic, toxic and other pathological
processes. In particular, the following experiment was
conducted in order to determine the correcting effect
of polyphenolic compounds on liver mitochondria in
conditions of toxic hepatitis (Figure 1).
In the experiments, a concentration of 2
0 μM of CaCl2,
which is considered as an inducer of mPTP, was used to
induce
mitochondrial
inhibition.
CaCl2-induced
inhibition of liver mitochondria isolated from healthy
rats (group 1) was taken as 100% as a control. According
to the results, it was found that the number of liver
mitochondria increased by 53.6% in 2 groups of rats
with toxic hepatitis compared to the control. As a
result of toxic hepatitis, an increase in Ca2+ loading of
liver mitochondria and a loss of membrane stability are
observed, which ensures a high permeability state of
the mPTP. Original image of the effects of glabra,
summax polyphenols and quercetin flavonoid on liver
mitochondrial dysfunction (mPTP permeability) in
CCl4-induced toxic hepatitis (Figure 1).
Figure 1. Original image on effects of glabra, summax polyphenols and flavonoid
quercetin on liver mitochondrial dysfunction (mPTP permeability) in CCl4-induced toxic
hepatitis
0
60
120
180
240
300
360
0,0
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Nazorat
TG
TG+glabra
TG+summax
TG+kversetin
– Ca
2+
Δ
A
540
Vaqt, sek.
Ca
2+
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We believe that tetrachloromethane, being a pro-
oxidant compound, causes an increase in the
production of ROS from the respiratory chain in
mitochondria. Increased levels of ROS in mitochondria
disrupt calcium signaling processes, leading to inner
membrane structures including membrane LPO [20-
24]. It causes a change in the conformation of the
membrane-enhanced
megachannel,
and
the
mitochondrial matrix is irreversibly distorted. An
increase in the permeability of mitochondria to water
and molecules dissolved in it can lead to its swelling
and a decrease in the calcium-paying capacity. Thus, an
increase in the amount of ROS in mitochondria can
cause a serious deficiency in the protection system
against oxidative damage. LPO not only leads to
increased ROS production, but can also damage
mitochondrial membrane integrity and shift the mPTP
to an open conformational state. The opening of MPTP
plays an important role in the mechanisms of necrosis
and apoptosis. In the conditions of toxic hepatitis, the
opening of the hepatic mPTP releases cytochrome c
from the matrix and lowers the mitochondrial
membrane potential after the appearance of
mitochondrial swelling. When the MPTP opens, its high
permeability increases the osmotic pressure of the
matrix plasma and causes the rupture of the
mitochondrial outer membrane. H+ flux is the driving
force for mitochondrial membrane potential and ATF
production, and its change can change membrane
dynamic behavior. It is evidenced that the suppression
of mitochondria under the influence of Ca2+ ions in the
conditions of toxic hepatitis may be based on the
above-mentioned mechanisms [6-10].
Figure 1. Effects of glabra, summax polyphenols and quercetin flavonoid on liver
mitochondrial dysfunction (mPTP permeability) in CCl4-induced toxic hepatitis (*p<0.05;
**p<0.01; n=5).
0
20
40
60
80
100
120
140
160
**
**
**
*
Δ
A
540
,
%
Nazorat (I guruh)
TG (II guruh)
TG+glabra (III guruh)
TG+summax (IV guruh)
TG+kversetin (V guruh)
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As a result of pharmacotherapy of group III rats with
CCl4-induced toxic hepatitis with glabra polyphenol at
a dose of 40 mg/kg div weight once a day for 15 days,
their It was found that the number of mitochondria
isolated from the liver was inhibited by 10.2% compared
to the indicators of group II with toxic hepatitis. Thus,
glabra polyphenol partially inhibits liver mitochondria
destruction in toxic hepatitis in rats (Fig. 2). By
continuing the experiments, group IV rats with toxic
hepatitis were treated with summax polyphenol at a
dose of 32 mg/kg per div weight for 15 days, resulting
in the destruction of liver mitochondria. was found to
be inhibited. In this case, it was found that the
proliferation of mitochondria isolated from the liver of
rats with hepatitis was inhibited by 30.1% compared to
the indicators of group II (Fig. 2). Thus, it was found
that summax polyphenol is 2.9 times more active than
glabra polyphenol in inhibiting mPTP permeability of
liver mitochondria of rats with toxic hepatitis.
One of the compounds that restore liver cells in toxic
hepatitis is the flavonoid quercetin, which in
experiments also restores mitochondrial dysfunction.
In our experiments, the effect of the hepatoprotective
compound quercetin, available as group V, on the
suppression of rat liver mitochondria was compared
with glabra and summax polyphenols. Group V rats
with toxic hepatitis were given a dose of 30 mg/kg of
the flavonoid quercetin for 15 days, and mitochondria
were extracted from their livers. According to the
obtained results, it was found that the Ca2+ ion-
dependent swelling of liver mitochondria of rats with
toxic hepatitis V was inhibited by 46.3% compared to
the indicators of group II (Fig. 1). So, quercetin
flavonoid has been found to be stronger than glabra
and summax polyphenol in inhibiting permeability of
liver mitochondria in hepatitis conditions.
0
0
20
40
60
80
100
120
140
160
Nazorat
Cyc A
TG
Cyc A
Cyc A
Cyc A
TG+glabra
TG+summax
Δ
A
5
4
0
,
mi
to
chon
d
ri
a
bo
’k
ishi
,
%
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Figure 3. Staging of rat liver mitochondria in toxic hepatitis under the influence of
Ca2+ ions and in the presence of 1 µM concentration of mPTP inhibitor cyclosporin A in
the incubation medium.
An increase in the load of Ca2+ ions in mitochondria
causes the mPTP to open. Many types of agents have
been found that cause mPTP opening. For example,
pro-oxidants, inducers, stress factors and hakazoo.
However, mPTP inhibitors are rare. In the experiments,
there is a classic inhibitor that inhibits the opening of
the mPTP, that is, mitochondrial strangulation. This
inhibitor is cyclosporine A, which inhibits mitochondrial
shunting by activating cyclophilin D, a component of
mPTP opening. cyclosporine A helps maintain
mitochondrial integrity by inhibiting mPTP opening,
maintains ATF production, and reduces cell death [22-
25].
In the above experiments, we were prompted to
conduct additional experiments in order to clarify
whether the inhibitory effect of polyphenolic
compounds on the suppression of liver mitochondria in
toxic hepatitis was actually caused by blocking the
mPTP opening. In subsequent experiments, the effect
of cyclosporine A on the size of mitochondria isolated
from the livers of rats with healthy, toxic hepatitis and
polyphenol-corrected toxic hepatitis was studied.
According to the obtained results, in rats of the control
group (healthy) the mitochondrial damage under the
influence of Ca2+ ions was recorded as 100%. It was
found that 100% inhibition of liver mitochondria of the
control group of rats under the influence of Ca2+ ions
and in the presence of mPTP inhibitor cyclosporine A in
the incubation medium was 100% (Fig. 3).
However, glabra and summax polyphenols were found
to inhibit mitochondrial destruction in toxic hepatitis
compared to group II indicators in the presence of
cyclosporin A (Fig. 4). Therefore, in the presence of
cyclosporin, the inhibition of mitochondrial function
under the influence of polyphenols may have occurred
through the activation of the mPTP component
cyclophilin D protein.
In the conditions of toxic hepatitis, it is possible to
increase the swelling of liver mitochondria, hydrolyze
the lipid structures of the inner and outer membranes
and lead to peroxidation. In the conditions of toxic
hepatitis, mPTP conformation opening of liver
mitochondria can also be realized by peroxide
oxidation of membrane lipids. Further experiments
were conducted in order to determine the LPO of the
inner and outer membrane of the liver mitochondria in
toxic hepatitis and to determine the effect of
polyphenol compounds on the amount of the final
product MDA.
One of the main changes in cell metabolism is the
activation of LPO. Under normal conditions, the
amount of LPO products remains in the tissues at a
certain level, because they are necessary for the
normal functioning of the div. They contribute to the
destruction of the destroyed components of the
respiratory chain in mitochondria and activate the
processes. It participates in cell proliferation and
differentiation, ion transport, regulation of cell
membrane permeability, destruction of damaged
chromosomes, etc. LPO in the cell is carried out by the
active form of oxygen [7, 9]
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Figure 4. Effects of glabra, summax and quercetin flavonoids on Fe2+/ascorbate-
induced LPO process of rat liver mitochondria under toxic hepatitis conditions. Original
record taken with V-5000 spectrophotometer.
A constant level of LPO products is maintained by the
antioxidant system of the cell. Under normal
conditions, molecular oxygen is a component of the
reaction that produces water molecules. The catalyst
of the reaction is cytochrome oxidase, which
contributes to the addition of four electrons to the
oxygen molecule. LPO causes disruption of cell
membrane components and subsequent membrane
integrity, which is accompanied by various pathological
processes,
in
particular,
inflammation,
neurodegenerative diseases, viral and toxic hepatitis,
etc. [11, 15]. As a result of LPO, the level of ROS
formation in mitochondria increases.
Bioactive compounds can stop the synthesis of ROS,
activate antioxidant enzymes or chelate metal ions
responsible for the formation of free radicals, purify
the cell from ROS []. One of these compounds is
polyphenolic compounds, which are distinguished
from other compounds by their high activity in
experiments. In this experiment, the effects of glabra,
summax polyphenols on Fe2+/ascorbate-induced LPO
of rat liver mitochondria under conditions of toxic
hepatitis were compared with quercetin (Figure 4). In
experiments, Fe2+/ascorbate is often used to generate
the mitochondrial membrane LPO process. In vivo
experiments, Fe2+/ascorbate was used to induce LPO
in liver mitochondrial membrane. According to the
obtained results, it was found that LPO induced by
Fe2+/ascorbate of liver mitochondria of group III rats
with toxic hepatitis injected with glabra polyphenol
was inhibited by 16.8% compared to group II with toxic
hepatitis. Glabra polyphenol reduced Fe2+/ascorbate-
induced LPO of rat liver mitochondria under conditions
0
60
120
180
240
300
360
0,0
0,3
0,4
0,5
0,6
0,7
0,8
TG
Nazorat
TG+kversetin
TG+summax
TG+glabra
Fe
2+
/ask.
Fe
2+
/ask.
Δ
A
540
Vaqt, sek.
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of toxic hepatitis. It was found that the LPO of the liver
mitochondria of group IV rats treated with summax
polyphenol pharmacotherapy with toxic hepatitis was
inhibited by 30.6% compared to the pathological group
(group II) (Fig. 4). Thus, it was shown that summax
polyphenol is stronger than glabra polyphenol in
reducing LPO of the liver mitochondria membrane in
toxic hepatitis. As a result of administration of
quercetin flavonoid to group B of the experiment with
toxic hepatitis, it was found that LPO induced by
Fe2+/ascorbate in liver mitochondria was inhibited by
75.6% compared to the results of group II (Fig. 4).
According to the obtained results, it was found that
LPO induced by Fe2+/ascorbate of liver mitochondria
of group III rats with toxic hepatitis injected with
glabra polyphenol was inhibited by 16.8% compared to
group II with toxic hepatitis. Glabra polyphenol
reduced Fe2+/ascorbate-induced LPO of rat liver
mitochondria under conditions of toxic hepatitis. It
was found that the LPO of the liver mitochondria of
group IV rats treated with summax polyphenol
pharmacotherapy with toxic hepatitis was inhibited by
30.6% compared to the pathological group (group II)
(Fig. 4). Thus, it was shown that summax polyphenol is
stronger than glabra polyphenol in reducing LPO of the
liver mitochondria membrane in toxic hepatitis. As a
result of administration of quercetin flavonoid to
group B of the experiment with toxic hepatitis, it was
found that LPO induced by Fe2+/ascorbate in liver
mitochondria was inhibited by 75.6% compared to the
results of group II (Fig. 4).
Figure 4. A). Effects of glabra, summax and quercetin flavonoids on Fe2+/ascorbate-
induced LPO process of rat liver mitochondria under toxic hepatitis conditions. B). Effects
of glabra, summax, and quercetin on the amount of MDA formed during LPO in rat liver
mitochondria in a model of toxic hepatitis. (**p<0.01; n=5).
0
0
50
100
150
200
250
Δ
A
540
,
%
TG
Nazorat
TG+kversetin
TG+summax
TG+glabra
**
**
**
**
0
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
4,0
MDA,
nmol
/m
in
.
mg
.
oqs
il
TG
Nazorat
TG+kversetin
TG+summax
TG+glabra
**
**
**
*
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The obtained results revealed that quercetin, glbara
and summax polyphenols had an inhibitory effect on
the LPO rate of the liver mitochondrial membrane
under conditions of toxic hepatitis. Among them,
quercetin flavonoid obtained as a standard
hepatoprotector, antioxidant compound showed a
more active inhibitory effect compared to glabra and
summax polyphenols. Acceleration of LPO process as a
result of CCl4-induced toxic hepatitis in rat liver
mitochondria caused an increase in MDA content.
Administration of glabra, summax polyphenols, and
quercetin flavonoids to toxic hepatitis models for the
purpose of correcting the LPO process for 15 days
caused a decrease in MDA, which in turn showed their
antioxidant properties.
CONCLUSION
In CCl4-induced toxic hepatitis, 15 days of
pharmacotherapy with glabra 40 mg/kg, summax
polyphenol 32 mg/kg, and quercetin 30 mg/kg div
weight for 15 days corrects liver mitochondrial
dysfunction. Summax polyphenol and quercetin
flavonoid partially close PTP of rat liver mitochondria
under conditions of toxic hepatitis, reduce membrane
permeabilization and increase mitoKATF-channel
activity. In the conditions of toxic hepatitis, glbara
polyphenol weakly inhibits the death of liver
mitochondria. Quercetin's astringent properties have
been found to be stronger than glabra and summax
polyphenols.
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