Circadian developmental rhythms of the experimental paracetamol hepatitis and the effect of hepatoprotectors on the activity of pro-oxidative / antioxidant and cytolytic processes




circadian rhythms, hepatoprotectors, paracetamol hepatitis, silymarin, antral, carsil, arginine glutamate


One of the current trends in modern experimental and clinical pharmacology is determination of the dependence of the effectiveness and toxicity of drugs on the time of day or season of the year.

Aim. To determine the characteristics of circadian rhythms of modern hepatoprotectors on the balance of antioxidant / prooxidant processes and the activity of cytolysis under conditions of acute paracetamol hepatitis in rats.

Materials and methods. Acute toxic hepatitis was caused by a single oral administration of paracetamol in the dose of 1000 g/kg of the body weight of animals in the morning (09.00), day (15.00), evening (21.00) and night (03.00) periods. In order to describe the effect on the lipid peroxidation/antioxidant system the intensity of the lipid peroxidation was measured by the level of tiobarbituric acid active products (TBA-AP). Determination of the level of recovered glutathione (RG), superoxide dismutase (SOD) and the catalase activity in the liver homogenate allowed characterizing the functional state of the antioxidant system of the animal organism. The activity of cytolytic processes was determined by the level of alanine aminotransferase (ALT) cytolysis marker in the blood serum.

Results. The circadian mass peak of the activity of the antioxidant system of the liver under physiological conditions in rats in the morning-day time and the minimum activity in the evening-night were determined. The experimental paracetamol hepatitis was characterized by peaks of the cytolytic process activity in the evening (21.00) and in the morning (09.00). The increase in the ALT activity by 3.3 and 2.5 times (p<0.05) coincides with a peak reduction of endogenous antioxidant (RG) in the morning by 1.4 times (p<0.05) and the minimal cytolytic changes during the day (15.00) and at night (03.00). It was found that there was the most marked effect of the phytohepatoprotector silymarin (carsil) and the synthetic hepatoprotector antral on the balance of antioxidant / prooxidant and cytolytic processes in the morning (09.00) and evening (21.00). It was confirmed by an increase in the level of RG by 1.2 times (p<0.05) and a decrease in the activity of ALT by 1.2-1.5 times (p<0.05) in relation to animals with hepatitis when using silymarin, as well as an increase in the SOD activity by 1.2 times (p<0.05), an increase in the level of RG by 1.3 and 1.4 times and a decrease in the activity of ALT by 1.3-1.5 times (p<0.05) when using antral. Arginine glutamate (“Glutargin”) increased the activity of the antioxidant system and suppressed cytolytic processes during the day (15.00) and at night (03.00) against the background of paracetamol hepatitis: an increase in the level of RG by 1.4 times (p<0.05) and a decrease in the activity of ALT in 1.2-1.3 times (p<0.05), respectively.

Conclusions. The circadian rhythms of the maximum severity of paracetamol hepatitis determined (at 21.00 and 09.00) should be taken into account in the experimental pharmacology when reproducing this model of liver damage. The antioxidant and anticytolytic action of silymarin and antral is maximally detected in the morning and evening, while the effect of arginine glutamate revealed during the day and at night. The chronopharmacological peculiarities of the effect of the hepatoprotectors studied on antioxidant / prooxidant and cytolytic processes should be taken into account when using them as reference values in the preclinical study of promising hepatoprotectors and in further chronopharmacological studies.

Author Biographies

S. M. Drogovoz, National University of Pharmacy

Doctor of Medicine (Dr. habil.), professor of the Pharmacology Department

O. M. Mishchenko, Institute of Qualification Improvement for Pharmacists of the National University of Pharmacy

Doctor of Pharmacy (Dr. habil.), professor, head of the Department of Clinical Pharmacology

K. O. Kalko, Institute of Qualification Improvement for Pharmacists of the National University of Pharmacy

Candidate of Pharmacy (Ph.D.), teaching assistant of the Department of Clinical Pharmacology

N. S. Bogdan, Higher state Educational Establishment “Bukovinian State Medical University”

Candidate of Pharmacy (Ph.D.), teaching assistant of the Department of Pharmacy

O. V. Gerush, Higher State Educational Establishment of Ukraine “Bukovinian State Medical University”

Candidate of Pharmacy (Ph.D.), associate professor, head of the Department of Pharmacy


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Pre-clinical studies of new drugs