Article

ISSN 0006-2979, Biochemistry (Moscow), 2024, Vol. 89, No. 11, pp. 1904-1910 © The Author(s) 2024. This article is an open access publication.

1904

Association of Peripheral Markers of Oxidative Stress

with Clinical Parameters and Inflammatory Factors

in Alcoholic Patients

Valentina D. Prokopieva

1,a

*, Tamara P. Vetlugina

, Elena V. Epimakhova

Anastasiya S. Boiko

, and Nikolay A. Bokhan

1,2

Mental Health Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences,

634014 Tomsk, Russia

Tomsk State University, 634050 Tomsk, Russia

e-mail: valyaprok@mail.ru

Received May 29, 2024

Revised July 26, 2024

Accepted August 24, 2024

Abstract— One of the fundamental problems in studying addiction is elucidation of mechanisms of alcohol

dependence(AD) development. Disturbances of cellular redox balance and inflammation play an important role

in AD pathogenesis. Deciphering associations between biological and clinical indicators can elucidate molecular

mechanisms of disease pathogenesis. The aim of the work was to study peripheral markers of oxidative stress

in patients with AD during early abstinence period and to identify their relationship with clinical parameters of

the disease and inflammatory factors. In total, 84 patients with AD were studied (average age, 44.3 ±  8.2 years).

The analyzed clinical parameters included patient’s age, age of alcohol withdrawal syndrome (AWS) formation,

disease duration, and AWS duration. The markers of oxidative stress determined in the blood plasma were

oxidation products of proteins (protein carbonyls, PCs), lipids (thiobarbituric acid-reactive products, TBA-RPs),

and DNA (8-hydroxy-2′-deoxyguanosine, 8-OH-dG). The content of inflammatory mediators, such as proinflam-

matory cytokines (IFNγ, IL-1β, IL-6, IL-8, IL-17A, TNFα) was determined in the blood serum. Blood samples of

80 conditionally healthy men (average age, 40.9±9.6 years) were used as a control. Patients with AD demon-

strated an increase in the content of PCs, TBA-RPs, and all analyzed cytokines (but not 8-OH-dG) compared

to the control individuals. There was a direct correlation between the TBA-RP content and disease duration

and inverse correlation of the PC content with the age of AWS formation and AWS duration. The content of

PCs demonstrated an inverse correlation with the IL-6 concentration in the blood plasma. We also observed a

positive correlation between 8-OH-dG and IL-6, TBA-RPs and IL-8, and TBA-RPs and TNFα. Therefore, the early

abstinence period in patients with AD was characterized by a pronounced oxidative stress and inflammation.

The obtained results expand the knowledge on the integrative contribution of oxidative stress and inflamma-

tory factors to the AD pathogenesis and can be used in the development of new therapies.

DOI: 10.1134/S000629792411004X

Keywords: oxidative stress markers, proinflammatory cytokines, alcohol dependence

Abbreviations: 8-OH-dG,8-hydroxy-2’-deoxyguanosine (8-oxo-7,8-dihydro-2′-deoxyguanosine); AWS, alcohol withdrawal syn-

drome; AD,alcohol dependence; IL, interleukin; LPO, lipid peroxidation; IFNγ, interferon gamma; PC, protein carbonyl;

TBA-RP, TBA-reactive product; TNFα, tumor necrosis factor alpha.

* To whom correspondence should be addressed.

INTRODUCTION

The studies of addiction have shown that simi-

larly to many pathological conditions, alcoholism (in

particular, alcohol dependence, AD) is accompanied by

the development of oxidative stress. Beside general

mechanisms of oxidative stress emergence, alcoholism

is characterized by specific sources of free radicals,

OXIDATIVE STRESS AND INFLAMMATION IN ALCOHOLISM 1905

BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024

including reactive oxygen species (ROS), associated

with the transformation of ethanol and its main me-

tabolite acetaldehyde in the body [1-3].

Alcohol passes through the blood-brain barrier,

which causes activation of microglia and leads to the

increased production of proinflammatory cytokines,

development of neuroinflammation in the central ner-

vous system, and impairment of neuroimmune com-

munications, thus affecting behavioral responses of

alcoholic patients  [4-6]. Long-term alcohol consump-

tion also weakens the intestinal barrier and promot-

ing release into the blood of bacterial components,

e.g., lipopolysaccharides (LPSs), that activate immune

system mainly through immune cell receptors (TLR4).

Activation of immune system causes increase in the

levels of circulating cytokines and promotes develop-

ment of inflammation and alcohol-mediated damage

to internal organs [7].

Because activated immune cells generate ROS,

the inflammatory process is always accompanied by

oxidative stress  [8,  9]. Impairments in the functioning

of antioxidant and immune defense systems caused

by the long-term alcohol consumption contribute to

the formation of concomitant somatic pathologies in

patients, which significantly reduces the efficacy of

standard treatment. New therapeutic approaches have

been developed based on the existing data on mo-

lecular mechanisms underlying the damaging effect

of ethanol on the cells of body organs and put into

practice. In particular, they include supplementing a

standard therapy with drugs aimed at the molecular

targets involved in the toxic effects of ethanol in or-

der to increase the efficacy of used treatment [10].

An information on the fundamental processes involved

in AD pathogenesis is essential for the improvement

of already existing and development of new treat-

ment methods. It can be obtained by studying oxida-

tive stress at different stages of AD and identifying its

clinical and biological associations.

The aim of this work was to investigate periph-

eral markers of oxidative stress in AD patients in the

early abstinence period and to identify their relation-

ship with AD clinical parameters and inflammatory

factors.

MATERIALS AND METHODS

Eighty-four male patients with alcoholism admit-

ted to the clinic of the Research Institute of Mental

Health with a diagnosis coded by ICD-10 as “mental

and behavioral disorders as a result of alcohol con-

sumption (dependence syndrome F10.21 and with-

drawal syndrome F10.30)” were studied. The patients

were 30 to 60 years old (average age, of 44.3 ±  8.2

years), with the disease duration of 13.6 ±  8.0 years.

Diagnostic assessment and clinical verification of di-

agnosis were performed by physicians of the Depart-

ment of Addictive States. For each patient, a stan-

dardized description card was filled that contained

general identifying data, clinical parameters, such as

patient’s age at the time of examination, age of the

alcohol withdrawal syndrome (AWS) formation, dis-

ease duration (calculated as a period of time from the

AWS formation to the date of examination), and du-

ration of AWS after alcohol withdrawal. As a control,

we used blood samples of 80 conditionally healthy

men (average age, 40.9 ±  9.6 years) who did not have

problems with alcohol consumption, as well as chron-

ic somatic diseases in the acute stage or symptoms of

acute infectious diseases. Thirty-seven control blood

samples were used to obtain plasma for the assess-

ment of oxidative stress markers; the other 43 samples

were used to obtain blood serum for the assessment

of inflammatory mediators.

Blood from alcoholic patients was collected on

days 3-5 of their admission to the hospital after alcohol

detoxification performed to remove toxic substances

from the body and to reduce the symptoms of AWS.

Peripheral venous blood from AD patients and control

individuals was collected in the morning on an empty

stomach using a sterile one-use holder Vacutainer sys-

tem (Becton Dickinson, USA) in heparin-coated tubes

(for plasma) or tubes containing coagulation activator

(for serum). The blood was centrifuged; serum and

plasma were aliquoted and stored at –80°C until use.

The content of protein oxidation products in

blood plasma was evaluated from the concentration

of protein carbonyls (PCs; nmol/mg protein) using a

method based on the reaction of PC derivatives with

2,4-dinitrophenylhydrazine (Panreac, Spain) with the

formation of 2,4-dinitrophenylhydrazones [11]. Total

protein concentration (mg/ml) was determined using

a Total Protein 120 kit (Cormay, Poland). The content

of LPO products were assessed from the concentra-

tion of thiobarbituric acid-reactive products (TBA-RPs;

nmol/ml) using a TBA AGAT kit (Agat-Med, Russia).

The content of the oxidative DNA damage product

8-hydroxy-2′-deoxyguanosine (8-OH-dG) was measured

with a DNA Damage Competitive Elisa Kit (Thermo

Fisher Scientific, USA) and expressed in ng/ml. Theop-

tical density of the oxidation products was determined

with an EPOCH spectrophotometer (BioTek Instru-

ments, USA).

Blood serum was analyzed for the concentration

(pg/ml) of the following proinflammatory cytokines:

interferon gamma (IFNγ); interleukin-1β (IL-1β); in-

terleukin-6 (IL-6); interleukin-8 (IL-8); interleukin-17A

(IL-17A); tumor necrosis factor alpha (TNFα). The as-

says were carried out with a MAGPIX multiplex analyz-

er (Luminex, USA) (Medical Genomics Center for Col-

lective Use, Tomsk National Research Medical Center)

PROKOPIEVA et al.1906

BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024

using MILLIPLEX MAP Human Cytokine/Chemokine

Magnetic Bead Panel reagent kits (Merck, Germany).

Statistical analysis was performed with SPSS

v. 23.0 for Windows; the data were presented as me-

dian and interquartile range Me [Q

-Q

], except for

the age of study participants and disease duration

that were presented as mean  ±  standard deviation

(M  ±  SD). The data were examined for the normality

of distribution using the Shapiro–Wilk test. The Mann–

Whitney test was used for the between-group com-

parison. Correlation analysis was performed using the

Spearman’s rank correlation coefficient. Correlations

and differences between the groups were considered

significant at p  <  0.05.

RESULTS

Table 1 shows the clinical data for the patients

in the study.

The study was performed in alcoholic patients

during the early abstinence period after alcohol de-

toxification.

Table 2 shows the results of comparative study of

peripheral oxidative stress markers in patients with

AD and healthy individuals.

Table 3 shows the concentration of proinflamma-

tory cytokines (inflammatory mediators) in alcoholic

patients.

The primary objective of our study was to identi-

fy the relationship between the oxidative stress mark-

ers, clinical parameters, and content of inflammatory

cytokines in the blood of patients with AD. The results

of correlation analysis are shown in Table 4.

DISCUSSION

Assessment of peripheral markers of oxidative

stress (products of lipid, protein, and DNA oxidation

in blood plasma) in patients with alcoholism in the

early abstinence period revealed the development

of a pronounced oxidative stress, as the concentra-

tions of PCs and TBA-RCs in the plasma of alcoholic

patients were significantly higher than in the control

individuals (Table2). A similar increase in the content

Table  1. Clinical parameters of alcoholic patients

(n = 84); Me [Q

-Q

]

Parameters Value

Age, years 44.50 [38.00-50.00]

Age of AWS formation, years 30.00 [25.00-35.00]

Disease duration, years 12.50 [7.00-19.00]

AWS duration, days 4.00 [2.00-4.00]

Table 2. Peripheral markers of oxidative stress in the plasma of alcoholic patients and healthy individuals;

Me [Q

-Q

]

Oxidative stress marker Alcoholic patients, n =84 Control, n=37 p between-group

PCs, nmol/mg protein 0.42 [0.35-0.49] 0.33 [0.27-0.39] <0.001

TBA-RPs, nmol/ml 2.97 [2.50-3.55] 2.40 [2.10-2.80] <0.001

8-OH-dG, ng/ml 13.30 [9.84-16.08] 12.84 [11.16-16.45] 0.908

Table 3. Concentrations of proinflammatory cytokines in the blood of alcoholic patients and healthy individuals;

Me [Q

-Q

]

Inflammatory cytokine Alcoholic patients, n =31 Control, pg/ml; n=43 p-value

IFNγ 32.46 [29.36-35.44] 3.07 [0.88-5.47] p< 0.001

IL-1β 5.56 [4.91-6.41] 0.68 [0.25-2.46] p< 0.001

IL-6 5.96 [4.74-10.47] 1.26 [0.35-4.06] p < 0.001

IL-8 26.38 [19.72-40.53] 8.59 [5.69-13.78] p < 0.001

IL-17A 24.27 [22.53-27.82] 2.83 [1.07-5.17] p< 0.001

TNFα 30.03 [28.55-38.67] 9.75 [7.00-12.49] p < 0.001

OXIDATIVE STRESS AND INFLAMMATION IN ALCOHOLISM 1907

BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024

Table 4. Correlation of peripheral oxidative stress

markers with clinical parameters and content of

inflammatory cytokines in alcoholic patients

Parameters

Spearman’s rank

correlation

coefficient (r

)

p-value

TBA-RP and disease

duration

0.201 0.049

PCs and age of AWS

formation

–0.245 0.025

PCs and AWS duration –0.246 0.024

PCs and IL-6 –0.620 0.003

8-OH-dG and IL-6 0.433 0.044

TBA-RPs and IL-8 0.457 0.049

TBA-RPs and TNFα 0.468 0.037

of peripheral oxidative stress markers, such as mal-

ondialdehyde (LPO product) and PCs in the serum

of patients with alcoholism has been reported in the

works of other authors [12, 13].

At the same time, the content of 8-OH-dG (product

of DNA oxidation) in AD patients did not differ from

the control (Table 2). Previously, we reported an in-

creased concentration of 8-OH-dG in the blood plasma

of AD patients with the AWS upon their admission to

the hospital [14]. Alcoholic patients with the AWS or

after 1 week of detoxification were also demonstrated

an increased level of 8-OH-dG [15]. This discrepancy

can be explained by the fact that the studies were con-

ducted in patients with different stages of the disease,

as well as by a variety of mechanisms that can affect

the level of DNA oxidation products in human blood

plasma. Chernikov et al.  [16] analyzed the reports

on the biomedical properties, mechanisms of action,

and possible therapeutic effects of such DNA metabo-

lites [16]. More than 30 oxidation products of nitrog-

enous bases are known, the most studied of which

are 8-oxo-7,8-dihydroguanine (8-oxo-dG) and 8-OH-dG.

Formation of 8-oxo-dG is the most common type of

oxidative damage of nucleic acids  [17], while 8-OH-dG

is one of the main oxidative stress biomarkers [15, 18].

Free 8-oxo-dG has been shown to act as a mediator

of stress signaling in cells that triggers and potenti-

ates inflammatory and immune responses in order

to maintain homeostasis upon the action of external

agents. 8-OH-dG also exhibits pronounced anti-inflam-

matory and antioxidant properties  [16]. Marmiy and

Esipov in their review  [19] on the biological role of

8-oxo-2′-dG and, in particular, its antioxidant and an-

ti-inflammatory properties, cited a number of reports,

in which the content of 8-oxo-2′-dG first increased un-

der the action of stress factors, but then returned to

the normal values or even decreased. The activity of

antioxidant and DNA repair enzymes significantly in-

creases during the compensation period. The question

whether DNA oxidation products upregulate expres-

sion of such enzymes or activation of the correspond-

ing genes is caused by some other factors remains

open. However, beside the fact that 8-OH-dG has been

successfully used as an oxidative stress marker for a

long time, there is evidence suggesting involvement of

this compound in the regulation of gene expression,

DNA repair, control of inflammatory and autoimmune

responses, and triggering of the antioxidant defense

[19]. In view of this, the absence of differences in the

levels of 8-OH-dG in the plasma of patients with AD

and control subjects in our study is quite understand-

able. This metabolite not only accumulates in the body

during oxidative stress, it is actively involved in the

regulation of metabolic processes, which, in turn, can

affect its concentration in blood plasma.

Assessment of proinflammatory cytokine levels

showed that the concentrations of all studied inflam-

matory mediators in the blood serum of alcoholic pa-

tients were significantly higher than in the control in-

dividuals (p  <  0.001 in all cases). The highest increase

(by more than an order of magnitude) was found for

the concentration of IFNγ (Table  3). Previously, the

studies of spontaneous production of cytokines (IFNγ,

IL-17A, IL-1Ra, IL-1β, IL-2, IL-6, IL-8, and TNFα) by im-

munocompetent cells revealed a significant increase

in the concentration of cytokines in the supernatants

of blood samples from patients with AD compared

to healthy individuals [20]. There was a correlation

between the spontaneous production of cytokines by

blood cells of patients with AD and products of pro-

tein and lipid oxidation in the blood plasma of these

patients [21], which indirectly indicated a stimulating

effect of ethanol and its metabolic products on immu-

nocompetent cells in  vivo. At the same time, the prod-

ucts of ethanol-induced oxidative stress can modulate

the synthesis of cytokines differently, as was demon-

strated in the alcohol consumption model in rats by

assessing the role of alcohol-induced oxidative stress

in the modulation of cytokine production in hepa-

tocytes and liver Kupffer cells [22]. The effect on the

synthesis of proinflammatory cytokines/chemokines

was mediated by the activity of NF-κB transcription

factor, histone acetylation, and impaired mRNA sta-

bility. Thus, hydrogen peroxide (H

) stimulated LPS-

induced cytokine/chemokine production in Kupffer

cells, while 4-hydroxynonenal displayed the inhibitory

effect.

Studying the correlations between oxidative stress

markers and clinical characteristics of AD revealed

negative associations of PC concentration with the

PROKOPIEVA et al.1908

BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024

age of AWS formation and AWS duration after alco-

hol withdrawal (Table4). Since mechanisms of AD for-

mation and development involve multiple molecular

pathways, it is impossible to explain the identified re-

lationships unambiguously. Nevertheless, we can defi-

nitely say that PCs participate in these mechanisms.

We also found a direct relationship between the

level of LPO products (TBA-RPs) and disease duration.

It is known that aging is associated with the increased

amounts of biomacromolecule oxidation products

[23-25]. Spiteller [25] provided evidence that LPO are

formed as a result of processes induced by changes

in the structure of cell membrane that occur in aging,

as well as under the influence of adverse factors, in

particular, systematic long-term alcohol consumption.

Structural changes in biological membranes under

the action of ethanol lead to the activation of mem-

brane-bound phospholipases, which induces the influx

of Ca

ions and activation of lipoxygenases. Lipoxy-

genases convert polyunsaturated fatty acids into lip-

id hydroperoxides that can be degraded by enzymes

into signaling compounds. This induces non-enzymatic

LPO, and the process of TBA-RP accumulation contin-

ues [24]. We found a correlation between the content

of TBA-RPs and disease duration in patients with AD.

The correlations between the oxidative stress

markers and the content of proinflammatory cyto-

kines found in our study confirm a close relationship

between inflammation and oxidative stress  [8,  9].

The relationship between the oxidative stress mark-

ers and IL-6 is of special significance, since IL-6 is the

most important inflammatory mediator that induces

the synthesis of acute phase proteins. We noted that

the strongest associations among identified correla-

tions were the inverse relationship between PCs and

IL-6 and direct relationship between 8-OH-dG and IL-6

(Table  4). As already mentioned, 8-OH-dG has been

found to exhibits pronounced antioxidant properties

[16,  19]. One of the explanations for the observed as-

sociations may be the following: the inflammatory

process upregulates IL-6, as well as promotes oxida-

tion of plasma macromolecules, including DNA, with

the formation of oxidation products (8-OH-dG), thus

leading to the direct relationship between the levels

of IL-6 and 8-OH-dG. Since 8-OH-dG has the antiox-

idant effect, its accumulation in the blood prevents

protein oxidation and reduces the concentration of

PCs in the blood, which leads to the negative correla-

tion between the IL-6 content and PC concentration

observed in our study.

Our explanation for the association of oxidative

stress markers with AD clinical parameters and in-

flammatory mediators is still a hypothesis. Further

research and more data are needed to identify the

relationship between the metabolic pathways at dif-

ferent stages of AD development.

CONCLUSION

We found that the early abstinence period in AD

patients is accompanied by a pronounced oxidative

stress and accumulation of products of protein and

lipid oxidation in the blood.

We also revealed the correlation between the

levels of oxidative stress markers and disease dura-

tion, age of AWS onset, and AWS duration, as well

as between the contents of PCs, TBA-RPs, 8-OH-dG,

and proinflammatory cytokines, the concentrations

of which were significantly increased in patients

with AD.

It was demonstrated that the studied peripheral

oxidative stress biomarkers reflect a combined contri-

bution of oxidative stress and inflammation to the AD

pathogenesis. The obtained data expand the knowl-

edge about pathogenesis of alcoholism and might be

helpful in the development of new treatment methods

that will include therapeutic agents aimed at normal-

izing the oxidative status and reducing inflammation.

Contributions. V.D.P., T.P.V., and N.A.B. developed

the concept and supervised the study; E.V.E. and A.S.B.

conducted the experiments; V.D.P., T.P.V., and E.V.E. dis-

cussed the study results and prepared the manuscript;

T.P.V. and N.A.B. edited the manuscript.

Funding. The study was carried out as part of

the State task no. 075-00712-24-00; research topic

no.122020200053-1.

Ethics declaration. All procedures performed

in human subjects met the ethical standards of the

National Research Ethics Committee and the Helsinki

Declaration of 1964 and its subsequent revisions or

comparable ethics standards. Voluntary informed con-

sent was obtained from each involved participant.

Thestudy was approved by the Local Ethics Commit-

tee at the Mental Health Research Institute of Tomsk

National Research Medical Center. The authors of this

work declare that they have no conflicts of interest.

Open access. This article is licensed under a Cre-

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