Keywords: Amino Acids; Derivatives; Liver Pathology
Abbreviations: BCAA: Branched Chain Hydrocarbon Amino Acids; AAA: Aromatic Amino Acid Metabolism; NE: Non-Essential
Mini Review
A mini review of literature data on the mechanisms of
formation of the stock of free amino acids and their derivatives in
liver pathology and methods for correcting metabolic imbalance.
The importance of amino acids in the biosynthesis of protein and
highly active biological compounds was the main prerequisite for
numerous studies of their content in body fluids and tissues in a
wide variety of experimental and pathological situations. In the
intermediate metabolism of amino acids and their derivatives, a
connecting role is played by in the integration of the main metabolic
flows [1-4]. The pool of free amino acids is represented by a rich set
of metabolically and functionally interconnected compounds, with
the concentrations being a regulatory factor at many key steps of
metabolism [5,6].
In connection with the foregoing, study of the mechanisms of
formation of the free amino acid pool in vivo is part of the most
important problem of contemporary biochemistry and clinical
medicine associated with targeted regulation of metabolic processes
in the human body by biologically active natural compounds.
Currently, the number of patients with pathology continues to
grow, with metabolic disorders playing a leading role in the genesis
of these pathologic states [4-6]. The most urgent in this case is the
problem of the pathogenetic role of disorders in the metabolism of
amino acids in hepatobiliary pathology, as well as the optimization
of the use of individual amino acids or their artificial mixtures
not only for replacement therapy, but also for targeted metabolic
correction of liver diseases [6-17]. In addition to disturbances in the
chain of reactions of carbohydrate, lipid and protein metabolisms
characteristic of liver damage, a pronounced amino acid imbalance
is observed in physiological fluids and tissues [18-20].
Thus, it was shown that an increase in blood methionine level
and a decrease in its excretion during exogenous loads with this
amino acid clearly correlate with clinical manifestations of diseases
accompanied by impaired liver function [21-24]. In addition,
the blood of patients with liver damage shows a decrease in the
concentration of the most important methionine degradation
product, cysteine, and a dramatic increase in the toxicity of
methionine [25,26]. Normally, up to 10 g of S-adenosylmethionine
is formed daily from methionine in the liver of humans in the S-adenosyl synthetase reaction. A decrease in its operating time,
which leads to a depletion of the cysteine pool, not only exacerbates
the negative nitrogen balance that develops as a result of liver
dysfunction, but also prevents detoxification reactions [27-31]. The
latter, as is known, are associated with transmethylation processes
in which S-adenosylmethionine plays the role of a donor of CH3
groups, and with the formation of glutathione, the synthesis of
which requires cysteine [32-35].
The search for ways to normalize the metabolism of sulfur-containing
amino acids in the last decade was the result of the use of
S-adenosylmethionine preparations for the treatment of hepatic
pathology. It was found that about half the total pool of methionine
in humans is catabolized in the liver, with 80% of it being converted
to S-adenosylmethionine. Subsequently, it was proved that the
latter methylates are not only proteins, histones, biogenic amines
and hormones, but also phospholipids of cell membranes. Thus,
S-adenosylmethionine is able to increase the fluidity of the hepatocyte
membranes. It is recommended as an additive in amino acid
mixtures for parenteral nutrition. At present, the most famous commercial
preparation of S-adenosylmethionine in Europe [36-39].
It has been shown that with pathology accompanied by
liver damage and a decrease in the activity of oxidation of other
substrates, the body can satisfy its energy requirements by 30-40%
due to the oxidation of branched chain hydrocarbon amino acids
(BCAA) - valine, leucine and isoleucine in peripheral tissues (the
main muscle) and gluconeogenesis [1-6,12-16]. Activation of BCAA
utilization along with their insufficient intake in such situations
leads to a decrease in their level in blood plasma [12-16,40]. In
addition, since the liver is the main site of aromatic amino acid
metabolism (AAA), in these cases the phenylalanine hydroxylation
rate and its conversion to tyrosine are reduced. The hydroxylation
coefficient (phenylalanine/tyrosine ratio) increases with hepatic
pathology. Disorders in the utilization of BCAA and AAA by the liver
during its pathology gave rise to the use of the APC / AAA molar
ratio to quantify the amino acid imbalance [41,42].
Thus, the imbalance between the hepatic utilization of the BCAA
and AAA is one of the signs of its pathology. The oral administration
of BCAA mixtures for these purposes increases their level while
reducing the AAA content in the blood plasma of patients with
liver failure. In the same study, the feasibility of using BCAA in
subclinical forms of hepatic encephalopathy was proved, and their
purpose under any catabolic conditions in the postoperative period
was justified since they stimulate protein biosynthesis in muscles
and liver and inhibit proteolysis, reducing negative nitrogen
balance [43,44]. The above served as the basis for the design and
use for parenteral nutrition in hepatology of specialized amino
acid mixtures enriched in BCAA. Theoretically, their purpose
in hepatic pathology is justified by the catabolic orientation of
metabolic processes, the ability of these amino acids to activate
protein biosynthesis and eliminate amino acid imbalance [12-16].
The results of the clinical testing of the oral administration of BCAA
served as the basis for production of the tablet form of a mixture of
these amino acids that is highly authoritative in the field of creating
new hepatoprotections by Dr. Falk [45-47].
A natural development of the “amino acid” correction of hepatic
pathology was the design of a number of highly specialized amino
sols with targeted action, characterized by a high content of BCAA
and a minimum of AAA, methionine and histidine. At the same
time, in such mixtures, the glycine concentration is reduced to 8%,
since the latter is one of the amino acids and acts as an inhibitory
neuromodulator in the central nervous system, and to activate the
detoxification and urea processes in them, the arginine content
was increased to 13%. Similar drugs are created and tested in
our country (FO-80 or “hepatamine”). Such FO-80 mixtures were
widely used abroad: Aminosteryl-Hepa (Germany), Levamin-
Hepa (Finland), Ner-OU (Japan) [5]. One of the main objectives
of drug therapy for liver damage is prevention of liver failure and
encephalopathy complicating it. The metabolism of proteins and
amino acids in the development of liver failure is disturbed in
the first place. In 63% of cases, acute liver failure is accompanied
by subclinical forms of hepatic encephalopathy [48-50]. In the
pathogenesis of the latter, an impairment in the metabolism of
amino acids is also given a leading place.
Thus, with the development of acute liver failure, azotemia is
noted, the plasma content of ammonia is increased, and that of
glutamine is increased in the cerebrospinal fluid, which indicates
accumulation of ammonia in the brain. Along with the activation
of protein degradation processes in the intestine and in the liver,
the urea formation cycle and AAA catabolism are inhibited and the
activation of BCAA degradation in the muscles occurs. An increase
in the concentration of ammonia in the brain activates glycolysis
and inhibits the tricarboxylic acid cycle, causing a decrease in
energy production. As a result of this, there is a disturbance in
the formation of excitatory amino acids glutamate and aspartate
in neurons with the formation of an excess of inhibitory
neuromodulator glutamine. In addition, this leads to a disturbed
synthesis of gamma-aminobutyrate. As a result, the balance of
excitatory and inhibitory amino acids changes. The effects of
ammonia in the brain are potentiated by neurotoxic products
formed during the breakdown of AAA, and the production of false
neurotransmitters is activated. The end result of these metabolic
disorders is dysfunction of the central nervous system with a
predominance of inhibition processes in it.
Thus, hepatobiliary pathology is characterized by significant
disturbances in the intermediate metabolism and a change in the
content of free amino acids (especially sulfur-containing, AAA
and BCAA) in the blood plasma and liver. Consequently, study of
amino acids is a promising field of present-day hepatology based
on the concept of the role of amino acids and their derivatives in
the pathogenesis of liver damage and the use of drugs in hepatic pathology. The reason for the use of taurine in liver diseases was
the relatively long-established ability of this compound to form
paired bile acids [49,51]. For humans, taurine is an almost essential
amino acid, and with prolonged parenteral nutrition or insufficient
intake of it, disturbances arise in the conjugation of bile acids and
lipid absorption. Therefore, the composition of artificial mixtures
for baby food (Semilak, USA) or our Tonus-1 mixtures (Belarus),
as well as amino sols used in pediatric practice (Vamin-Lact -
Sweden, Levamin-Lact - Finland), supplementary contains taurine
in amounts that meet the daily requirements. At present, it has
been shown that taurine, in addition to its participation in the
synthesis of paired bile acids, is a neurotransmitter and modulator
in the central nervous system, a regulator of membrane excitability
in the heart, an agent that actively affects the endocrine and
reproductive functions of animals, protecting cell membranes from
toxic substances . All this put it in a number of effective means of
influencing the functional systems of the body and aroused quite
justified interest not only of biochemists and physiologists, but also
of clinicians in this natural metabolite of the animal organism. A 4%
taurine solution under the name “Taufone” is used only in the form
of eye drops and sub-conjunctival injections in ophthalmology as a
stimulator of regeneration processes [2,12].
In studying the special pharmaceutical and biological activity of
taurine, it was established that the compound has hepatoprotective
and radioprotective properties. So, prescribed in various doses and
modes of administration, taurine increases the survival of animals,
prevents depression of blood cells and weight coefficients of
lymphoid organs. In the anti-radiation effect, it is not inferior to the
reference drugs hexamine and cysteamine, comparing favorably
with their low toxicity and the predicted absence of adverse
reactions undesirable for the body, as well as the contraindication
to use. It has been proven that taurine exhibits hepatoprotective
properties: it activates metabolic processes in the liver, increases its
resistance to pathogenic effects and activates the restoration of its
functions in various injuries [2,12,52-54]. Taurine is slightly toxic,
does not cumulate in the body, does not have an irritant effect, does
not affect reproductive function and offspring, does not exhibit
allergenic properties and does not adversely affect the immune
system. With its chronic prescription, the changes occurring in
morphological, physiological, and biochemical parameters are
not damaging, reversible, and return to the initial level after drug
withdrawal within 8–10 days [12].
Therefore, our efforts were focused on the study of the specific
metabolic activity of taurine as a regulator of amino acid metabolism,
hepatoprotective and radioprotective drug and a component of
artificial amino acid mixtures. Ultimately, this part of the work was
almost completed by the development for the tablet dosage form of
this drug, and clinical trials of taurine tablets as hepatoprotective
and radioprotective agents according to the specific indications for
use are being completed in specialized clinics. In connection with
the latter, it was especially important to study the mechanisms of
biosynthesis, as well as the formation of an intracellular pool of
sulfur-containing amino acids and a functionally active pool of the
most important product of their degradation, taurine [1-3].
We have shown that a single intraperitoneal administration
of taurine at a dose of 1/10 LD50 causes an increase in the
concentration of this compound in the liver and blood plasma of rats
and a decrease in the levels of methionine, glycogenic amino acids,
BCAA and AAA. In addition, in vitro taurine at concentrations of 10–
6–10–7 M increases the antiradical activity of liver homogenates,
their content of phosphatidylcholine, phosphoethanolamine and
reduces the level of ethanolamine [6]. Supplementary in vivo
administration of taurine increased the concentrations of reduced
glutathione, CoA, 2-oxoglutarate, the NAD/NADH ratio, activated
mitochondrial decarboxylases and transaminases and reduced the
concentration of glutamic acid, the ratio of BCAA / AAA, acetyl-
CoA / CoA in the liver. All of the above proves that increasing the
concentration of taurine activates glycolysis and the utilization of
carbon skeletons of amino acids in the tricarboxylic acid cycle in the
liver [12]. Metabolic prerequisites arising against the background
of an increased content of taurine in the body, thereby prove the
advisability of including this compound in the composition of
artificial mixtures of amino acids for parenteral nutrition [55-57].
A statistical model constructed for rat liver revealed a
dependence of the level of BCAA on taurine content, which suggests
its effect on glucose-alanine cycle activity, gluconeogenesis, and
utilization of these amino acids in the citric acid cycle [5]. Based
on the mathematical models created for the liver and blood
plasma, it can be assumed that an increase in the concentration
of taurine in the blood or liver upon activation of its synthesis or
against an exogenous load will contribute to a decrease in the level
of glycogenic amino acids [6,12]. Studies were also carried out of
the patterns of formation of the amino acid pool in the liver, blood
plasma and bile of patients against the background of functionally
reversible injuries of the hepatobiliary system in acute and chronic
cholecystitis. In our studies [1-6,12-16], it was shown that both
acute and chronic forms of cholecystitis are accompanied by hyper
aminoacidemia mainly due to glycogenic, aromatic and sulfurcontaining,
as well as amino acids and their derivatives, markers
of liver antitoxic function (urea, ammonia, gamma-aminobutyrate).
Changes in the content of these compounds were more pronounced
in the chronic form of the disease, especially due to an increase in
the total pool of sulfur-containing amino acids.
The dependence found by us was confirmed by the high efficiency
of the use of the Vamin amino amine in the clinic. Metabolic
correction of changes induced by operating trauma and inflammation
of the gallbladder was effective in the absence of pronounced
metabolic, functional and morphological changes in the liver and
contributed to a decrease in the frequency of postoperative complications
[1-6,58-62]. In the liver of animals with experimental
cholestasis, a pronounced tendency to an increase in the total stock of free amino acids was observed along with the almost fivefold decrease
in the ratio of essential amino acids to non-essential (NE)
ones. It is characteristic that these changes related primarily to glycogenic
amino acids, a metabolic disturbance in which in the liver
is one of the characteristic signs that occur even at early stages of
hepatobiliary pathology. On enrichment of the stock with free sulfur-
containing amino acids and their derivatives, a three-fold decrease
in the Fisher index (BCAA/AAA) was clearly noticed [3].
An additional administration of taurine in experimental
cholestasis had a normalizing effect on the levels of the studied
compounds in the liver and blood plasma of animals. From the
results reflecting the regularities of the formation of a pool of free
amino acids in hepatocytes of control and experimental animals, it
is obvious that the metabolic activity of hepatocytes isolated from
the “cholestatic” liver was reduced with respect to de novo amino
acid synthesis [5]. In the situation of experimental cholestasis,
we revealed the general patterns of the formation of amino acid
imbalance at the tissue (liver) and cellular (isolated hepatocytes)
levels and found metabolic preconditions justifying the feasibility of
including taurine in the composition of artificial mixtures of amino
acids for parenteral nutrition in extrahepatic cholestasis [12]. The
patterns of formation of the amino acid pool underdeveloped liver
failure were studied by us at the stages of surgical elimination of
biliary hypertension in 147 patients with subhepatic jaundice.
The amino acid imbalance in the blood plasma of this group of
patients was characterized by hyper aminoacidemia that was in
equal measure due to both NEAA and EAA, a drastic decrease in the
concentration of BCAA and a reduction in the ratio of BCAA /AAA.
Characteristic of blood plasma was a dramatic increase in
the concentration of sulfur-containing amino acids or formation
of paired compounds with bile acids or amino acids. Changes
in the content of the studied compounds in the liver due to its
insufficiency as a whole indicate an inhibition of reactions of amino
acid synthesis in the liver, their entry into bile, and a decrease in
the activity of enterohepatic recirculation [4]. Thus, extrahepatic
cholestasis under developing liver failure is characterized by a
pronounced amino acid imbalance which is formed mainly due to
a change in the levels of glycogenic and sulfur-containing amino
acids. A linear discriminant analysis of the amino acid pool of liver
biopsy samples of these patients showed that, despite the increase
in the content of precursors, the level of taurine did not essentially
differ from the control values. Obviously, in such a situation, an
increase in the concentration of taurine in the liver can be achieved
only due to its exogenous administration. Mathematical modeling
of the formation of the free amino acid pool in the liver justifies
the feasibility of additional exogenous administration of taurine in
hepatobiliary pathology [12].
From the first day after application of a laparoscopic cholecystomy, it turned out that the introduction into the bile ducts of 60 ml of a 4% solution of taurine (Taufone), dissolved in 500 ml of an isotonic solution of sodium chloride, under the pressure of a 140-180 mm water column in combination with intravenous administration of 400 ml Polyamine led to controlled decompression, correction of amino acid imbalance and a significant decrease in the manifestations of liver failure [1]. Thus, against the background of functionally reversible or morphological changes in the liver combined with hepatobiliary pathology, qualitatively similar metabolic disorders are formed in humans, leading to an amino acid imbalance and an increase in the concentration of sulfur-containing, aromatic and glycogenic amino acids in the liver and blood plasma.
Conclusion
Based on the results, we substantiated the effectiveness of using amino sols enriched with sulfur-containing amino acids or taurine to normalize the amino acid imbalance and the functional state of the liver, in order to diagnose and treat the initial stages of its damage. The changes in the level of free amino acids of the liver, blood plasma and bile are quite specific and informative for assessing the functional state of the liver, diagnosing and optimizing the metabolic correction of hepatobiliary pathology, and the prescription of taurine and special artificial mixtures of amino acids in the pathology studied aids in normalization of the amino acid imbalance and clinical and biochemical parameters as well as reduces the frequency of postoperative complications and the length of stay of patients in hospital.
Acknowledgement
None.
Conflict of Interest
No conflict of interest.
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