Evaluation of silymarin and berberine efficiencies in the self-emulsifying drug delivery systemin paracetamol-induced experimental toxic liver injury

The hepatoprotective properties of the silymarin and the plant alkaloid berberine combinationin experimental paracetamol-inducedliver damage were studied. Silymarin was obtained from milk thistle seeds. The conditions for extraction of flavonolignans (silymarin) were optimized. 70 % ethyl alcohol, ethyl acetate and water were used as extractants. It was shown that the optimal conditions for the extraction of flavonolignans in order to obtain the maximum yield of flavonolignans were alcohol extraction in a Soxhlet apparatus. The experiment showed that the combined of silymarin and berberine was greater than their individual actions, which most effectively permitted stabilization of hepatocyte membranes and prevented altering their integrity in paracetamol-induced toxic liver damage. The self-emulsifying system with silymarin and berberine to a greater extent a significant extent prevented dystrophic changes in hepatocytes and necrosis in liver tissue, reduced hyperfermentemia in rat blood serum, prevented disturbance in the activity of thioredoxin reductase and enzymes of the glutathione antioxidant system and there by more effectively prevented hepatocyte functional impairment.

silymarin, milk thistle, berberine, self-emulsifying system, toxic hepatitis, paracetamol

1. Gillessen A., Schmidt H. H. Silymarin as supportive treatment in liver diseases: a narrative review. Advances in Therapy, 2020, vol. 37, no. 4, pp. 1279–1301. https://doi.org/10.1007/s12325-020-01251-y

2. Javed S., Kohli K., Ali V. Reassessing bioavailability of silymarin. Alternative Medicine Review, 2011, vol. 16, no. 3, pp. 239–249.

3. Wang K., Feng X., Chai L., Cao S., Qiu F. The metabolism of berberine and its contribution to the pharmacological effects. Drug Metabolism Reviews, 2017, vol. 49, no. 2, pp. 139–157. https://doi.org/10.1080/03602532.2017.1306544

4. Zverinsky I. V., Melnichenko N. G., Poplavsky V. A., Sutsko I. P., Telegin P. G., Shlyahtun A. G. The effect of berberine administration to rats on the functional state of liver after common bile duct ligation. Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 2012, vol. 6, no. 2, pp 159–163. https://doi.org/10.1134/s1990750812020163

5. Zverinsky I. V., Zverinskaya H. G., Sutsko I. P., Telegin P. G., Shlyahtun A. G. Effects of berberine on the recovery of rat liver xenobiotic-metabolizing enzymes after partial hepatectomy. Biomeditsinskaya khimiya = Biomedical Chemistry, 2015, vol. 61, no 3, pp. 381–383 (in Russian). https://doi.org/10.18097/pbmc20156103381

6. Liu C.-S., Zheng Y.-R., Zhang Y.-F., Long X.-Y. Research progress on berberine with a special focus on its oral bioavailability. Fitoterapia, 2016, vol. 109, pp. 274–282. https://doi.org/10.1016/j.fitote.2016.02.001

7. Zhou S., Lim L. Y., Chowbay B. Herbal modulation of P-glycoprotein. Drug Metabolism Reviews, 2004, vol. 36, no. 1, pp. 57–104. https://doi.org/10.1081/dmr-120028427

8. Dokania S., Joshi A. K. Self-microemulsifying drug delivery system (SMEDDS) – challenges and road ahead. Drug Delivery, 2015, vol. 22, no. 6, pp. 675–690. https://doi.org/10.3109/10717544.2014.896058

9. Vergun О., Borisevich S., Kamyschnikov V. Acute paracetamol intoxication, diagnostics. Laboratornaya diagnostika. Vostochnaya Evropa = Laboratory diagnostics. Eastern Europe, 2015, no. 2 (14), pp. 113–118 (in Russian).

10. Bhushan B., Apte U. Liver regeneration after acetaminophen hepatotoxicity: mechanisms and therapeutic opportunities. American Journal of Pathology, 2019, vol. 189, no. 4, pp. 719–729. https://doi.org/10.1016/j.ajpath.2018.12.006

11. Barkovskii E. V., Bokut’ S. B., Borodinskii A. N., Buko V. U., Valentyukevich O. I., Gritsuk A. I. [et al.]. Modern problems of biochemistry. Research methods. Minsk, Vysheishaya shkola Publ., 2013, pp. 158–192 (in Russian).

12. Tamura T., Stadtman T. C. A new selenoprotein from human lung adenocarcinoma cells: purification, properties and thioredoxin activity. Proceedings of the National Academy of Sciences, 1996, vol. 93, no. 3, pp. 1006–1011. https://doi.org/10.1073/pnas.93.3.1006

13. Balamir A. NADP-linked isocitrate dehydrogenase from beef liver: a new method of purification and the effect of metal ion cofactor on its stability. Biochemical Medicine, 1983, vol. 29, no. 2, pp. 194–206. https://doi.org/10.1016/0006-2944(83)90040-6

14. Ghanem C. I., Pérez M. J., Manautou J. E., Mottino A. D. Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity. Pharmacological Research, 2016, vol. 109, pp. 119–131. https://doi.org/10.1016/j.phrs.2016.02.020

15. Sut’ko I. P., Shlyahtun A. G., Titko O. V., Yankevich N. V., Kolodko A. V., Telegin P. G., Zverinsky I. V. Experimental evaluation of berberine and silymarin efficiencies in the self-emulsifying drug delivery system for enhancing their hepatoprotective activities under toxic hepatitis. Vestnik Smolenskoi gosudarstvennoi medicinskoi akademii = Vestnik of the Smolensk State Medical Academy, 2019, vol. 18, no. 6, pp. 31–39 (in Russian).