Features of liver ultrastructure of rat exposed by antiretroviral drug tenofovir disoproxil fumarate in combination with S-adenosylmethionine

Ultrastructural changes in the liver of rats after 7and 21-days intragastric administration of tenofovir disoproxil fumarate (TDF) at a dose of 50 mg/kg/daily and correction of the revealed violations by S-adenosylmethionine (SAM) were described. Exposure of TDF for 7 days causes mild dystrophic changes in a small proportion of hepatocytes. The 21-day effect of TDF in the hepatocytes of the periportal zones shows the development of moderately pronounced dystrophy with a decrease in protein-synthetic function and slight changes in the structure of mitochondria. At both periods of administration, TDF leads to the death of single cells of the liver parenchyma and reactive intralobular inflammatory infiltration. The use of SAM on long-term administration of TDF does not reduce the intensity of core liver infiltration, but prevents the development of dystrophy of peripоrtal hepatocytes and normalizes the amount of lipid inclusions in parenchymal cells of the organ.

1. Gallant J. E., Deresinski S. Tenofovir disoproxil fumarate. Clinical Infectious Diseases, 2003, vol. 37, no. 7, pp. 944- 950. https://doi.org/10.1086/378068

2. Fung H. B., Stone E. A., Piacenti F. J. Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection. Clinical Therapeutics, 2002, vol. 24, no. 10, pp. 1515-1548. https://doi.org/10.1016/s01492918(02)80058-3

3. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. June 2016, Geneva, Switzerland. Available at: https://www.who.int/hiv/pub/arv/arv-2016/en (accessed 31 May 2019).

4. World Health Organization. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV. December 2018, Geneva, Switzerland. Available at: https://www.who.int/hiv/pub/guidelines/ARV2018update/en (accessed 31 May 2019).

5. Ribera E., Paradiñeiro J. C., Curran A., Sauleda S., García-Arumí E., Castella E. [et al.]. Improvements in subcutaneous fat, lipid profile, and parameters of mitochondrial toxicity in patients with peripheral lipoatrophy when stavudine is switched to tenofovir (LIPOTEST study). HIV Clinical Trials, 2008, vol. 9, no. 6, pp. 407-417. https://doi.org/10.1310/hct0906-407

6. Kamara D. A., Smith C., Ryom L., Reiss P., Rickenbach M., Phillips A. [et al.]. Longitudinal analysis of the associations between antiretroviral therapy, viraemia and immunosuppression with lipid levels: the D:A:D study. Antiviral Therapy, 2016, vol. 21, no. 6, pp. 495-506. https://doi.org/10.3851/IMP3051

7. Jamieson L., Evans D., Brennan A. T., Moyo F., Spencer D., Mahomed K., Maskew M., Long L., Rosen S., Fox M. P. Changes in elevated cholesterol in the era of tenofovir in South Africa: risk factors, clinical management and outcomes. HIV Medicine, 2017, vol. 18, no. 8, pp. 595-603. https://doi.org/10.1111/hiv.12495

8. Kovari H., Weber R. Influence of antiretroviral therapy on liver disease. Current Opinion in HIV and AIDS, 2011, vol. 6, no. 4, pp. 272-277. https://doi.org/10.1097/COH.0b013e3283473405

9. Kosi L., Reiberger T., Payer B. A., Grabmeier-Pfistershammer K., Strassl R., Rieger A., Peck-Radosavljevic M. Fiveyear on-treatment efficacy of lamivudine-, tenofovirand tenofovir + emtricitabine-based HAART in HBV-HIV-coinfected patients. Journal of Viral Hepatitis, 2012, vol. 19, no. 11, pp. 801-810. https://doi.org/10.1111/j.1365-2893.2012.01601.x

10. . Alvarez-Uria G., Ratcliffe L., Vilar J. Long-term outcome of tenofovir disoproxil fumarate use against hepatitis B in an HIV-coinfected cohort. HIV Medicine, 2009, vol. 10, no. 5, pp. 269-273. https://doi.org/10.1111/j.1468-1293.2008.00683.x

11. Fung S., Kwan P., Fabri M., Horban A., Pelemis M., Hann H. W. [et al.]. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology, 2014, vol. 146, no. 4, pp. 980-988.e1. https://doi.org/10.1053/j.gastro.2013.12.028

12. Hemkens L. G., Ewald H., Santini-Oliveira M., Bühler J. E., Vuichard D., Schandelmaier S., Stöckle M., Briel M., Bucher H. C. Comparative effectiveness of tenofovir in treatment-naïve HIV-infected patients: systematic review and metaanalysis. HIV Clinical Trials, 2015, vol. 16, no. 5, pp. 178-189. https://doi.org/10.1179/1945577115Y.0000000004

13. Echenique I. A., Rich J. D. EFV/FTC/TDF-associated hepatotoxicity: a case report and review. Aids Patient Care and STDs, 2013, vol. 27, no. 9, pp. 493-497. https://doi.org/10.1089/apc.2013.0008

14. Kang M. K., Park J. G. Tenofovir disoproxil fumarate-induced severe liver injury in a patient with chronic hepatitis B virus infection. Digestive and Liver Disease, 2018, vol. 50, no. 6, pp. 628-630. https://doi.org/10.1016/j.dld.2018.03.013

15. Adaramoye O. A., Adewumi O. M., Adesanoye O. A., Faokunla O. O., Farombi E. O. Effect of tenofovir, an antiretroviral drug, on hepatic and renal functional indices of Wistar rats: protective role of vitamin E. Journal of Basic and Clinical Physiology and Pharmacology, 2012, vol. 23, no. 2, pp. 69-75. https://doi.org/10.1515/jbcpp.2011.0042

16. Ng H. H., Stock H., Rausch L., Bunin D., Wang A., Brill S., Gow J., Mirsalis J. C. Tenofovir disoproxil fumarate: toxicity, toxicokinetics, and toxicogenomics analysis after 13 weeks of oral administration in mice. International Journal of Toxicology, 2015, vol. 34, no. 1, pp. 4-10. https://doi.org/10.1177/1091581814565669

17. Peter A. I., Naidu E. C., Akang E., Ogedengbe O. O., Offor U., Rambharose S., Kalhapure R., Chuturgoon A., Goven der T., Azu O. O. Investigating organ toxicity profile of tenofovir and tenofovir nanoparticle on the liver and kidney: experimental animal study. Toxicological Research, 2018, vol. 34, no. 3, pp. 221-229. https://doi.org/10.5487/TR.2018.34.3.221

18. Das S., Hajnóczky N., Antony A. N., Csordás G., Gaspers L. D., Clemens D. L., Hoek J. B., Hajnóczky G. Mitochondrial morphology and dynamics in hepatocytes from normal and ethanol-fed rats. Pflügers Archiv - European Journal of Physiology, 2012, vol. 464, no. 1, pp. 101-109. https://doi.org/10.1007/s00424-012-1100-4

19. Chen Y., Lv L., Jiang Z., Yang H., Li S., Jiang Y. Mitofusin 2 protects hepatocyte mitochondrial function from damage induced by GCDCA. PLoS ONE, 2013, vol. 8, no. 6, e65455. https://doi.org/10.1007/s00424-012-1100-4

20. Kim S.-J., Syed G. H., Khan M., Chiu W.-W., Sohail M. A., Gish R. G., Siddiqui A. Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence. Proceedings of the National Academy of Sciences, 2014, vol. 111, no. 17, pp. 6413-6418. https://doi.org/10.1073/pnas.1321114111

21. Kageyama Y., Zhang Z., Roda R., Fukaya M., Wakabayashi J., Wakabayashi N., Kensler T. W., Reddy P. H., Iijima M., Sesaki H. Mitochondrial division ensures the survival of postmitotic neurons by suppressing oxidative damage. Journal of Cell Biology, 2012, vol. 197, no. 4, pp. 535-551. https://doi.org/10.1083/jcb.201110034