vestimИзвестия Национальной академии наук Беларуси. Серия медицинских наукProceedings of the National Academy of Sciences of Belarus, Medical series1814-60232524-2350The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1814-6023-2020-17-1-55-63vestim-660Research ArticleКЛИНИЧЕСКАЯ И ЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНАCLINICAL AND EXPERIMENTAL MEDICINEАсаблівасці ўльтраструктуры печані пацукоў пры ўздзеянні анты рэтравіруснага прэпарата тэнафавіра дзіcапраксіл фумарат у спалучэнні з S-адэназілметыянінамFeatures of liver ultrastructure of rat exposed by antiretroviral drug tenofovir disoproxil fumarate in combination with S-adenosylmethionineАстроўскаяА. Б.AstrowskajaA. B.

Островская Оксана Борисовна – кандидат биологических наук, доцент, старший научный  сотрудник

ул. Горького, 80, 230015, г. Гродно

Aksana B. Astrowskaja – Ph. D. (Biol.), Assistant Professor, Senior researcher

80, Gorky Str., 230015, Grodno

astrowskaja@gmail.comКраўчукР. I.KrauchukR. I.

Кравчук Римма Ивановна – кандидат биологических наук, старший научный сотрудник

ул. Горького, 80, 230015, г. Гродно

Ryma I. Krauchuk – Ph. D. (Biol.), Senior researcher

80, Gorky Str., 230015, Grodno

rikravchuk@gmail.comКурбатМ. М.KurbatM. M.

Курбат Михаил Николаевич – кандидат медицинских наук, доцент, заведующий лабораторией

ул. Горького, 80, 230015, г. Гродно

Mikhail M. Kurbat – Ph. D. (Med.), Assistant Professor, Head of the Laboratory

80, Gorky Str., 230015, Grodno

vwmisha@mail.ruГродзенскі дзяржаўны медыцынскі ўніверсітэтGrodna State Medical University2020180320201715563Copyright © Астроўская А.Б., Краўчук Р.I., Курбат М.М., 20202020Астроўская А.Б., Краўчук Р.I., Курбат М.М.Astrowskaja A.B., Krauchuk R.I., Kurbat M.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestimed.belnauka.by/jour/article/view/660

Описаны ультраструктурные изменения печени крыс при 7и 21-суточном внутрижелудочном введении тенофовира дизопроксил фумарат (tenofovir disoproxil fumarate, TDF) в дозе 50 мг/кг/сут и при коррекции выявленных нарушений S-аденозилметионином (S-adenosylmethionine, SAM). Воздействие TDF в течение 7 сут вызывает слабо выраженные дистрофические изменения небольшой доли гепатоцитов. После 21-суточного воздействия TDF в гепатоцитах перипортальных зон отмечается развитие умеренно выраженной дистрофии со снижением белок-синтетической функции и слабо выраженными изменениями структуры митохондрий. При обоих сроках введения TDF провоцирует гибель единичных клеток паренхимы печени и реактивную внутридольковую воспалительную инфильтрацию. Использование SAM на фоне длительного назначения TDF не приводит к снижению интенсивности внутридольковой инфильтрации печени, но предотвращает развитие дистрофии перипортальных гепатоцитов, нормализует количество липидных включений в паренхиматозных клетках органа.

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.

печеньультраструктураtenofovir disoproxil fumarateS-adenosylmethionineliverultrastructuretenofovir disoproxil fumarateS-adenosylmethionineReferencesGallant, J. E. Tenofovir disoproxil fumarate / J. E. Gallant, S. Deresinski // Clin. Infect. Dis. – 2003. – Vol. 37, N 7. – P. 944–950. https://doi.org/10.1086/378068Gallant J. E., Deresinski S. Tenofovir disoproxil fumarate. Clinical Infectious Diseases, 2003, vol. 37, no. 7, pp. 944– 950. https://doi.org/10.1086/378068Fung, H. B. Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection / H. B. Fung, E. A. Stone, F. J. Piacenti // Clin. Ther. – 2002. – Vol. 24, N 10. – Р. 1515–1548. https://doi.org/10.1016/s0149-2918(02)80058-3Fung 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)80058-3Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, June 2016. [Electronic resource] // World Health Organization Geneva, Switzerland. – Mode of access : https://www.who.int/hiv/pub/arv/arv2016/en/ – Date of access : 31.05.2019.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).Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV, December 2018. [Electronic resource] // World Health Organization, Geneva, Switzerland. – Mode of access : https://www.who.int/hiv/pub/guidelines/ARV2018update/en/ – Date of access : 31.05.2019.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).Improvements in subcutaneous fat, lipid profile, and parameters of mitochondrial toxicity in patients with peripheral lipoatrophy when stavudine is switched to tenofovir (LIPOTEST study) / E. Ribera [et al.] // HIV Clin. Trials. – 2008. – Vol. 9, N 6. – Р. 407–417. https://doi.org/10.1310/hct0906-407Ribera 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/hct0906-407Longitudinal analysis of the associations between antiretroviral therapy, viraemia and immunosuppression with lipid levels: the D:A:D study / D. A. Kamara [et al.] // Antivir. Ther. – 2016. – Vol. 21, N 6. – P. 495–506. https://doi.org/10.3851/IMP3051Kamara 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/IMP3051Changes in elevated cholesterol in the era of tenofovir in South Africa: risk factors, clinical management and outcomes / L. Jamieson [et al.] // HIV Med. – 2017. – Vol. 18, N 8. – P. 595–603. https://doi.org/10.1111/hiv.12495Jamieson 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.12495Kovari, H. Influence of antiretroviral therapy on liver disease / H. Kovari, R. Weber // Curr. Opin. HIV AIDS. – 2011. – Vol. 6, N 4. – Р. 272–277. https://doi.org/10.1097/COH.0b013e3283473405Kovari 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.0b013e3283473405Five-year on-treatment efficacy of lamivudine-, tenofovirand tenofovir + emtricitabine-based HAART in HBV-HIVcoinfected patients / L. Kosi [et al.] // J. Viral. Hepat. – 2012. – Vol. 19, N 11. – P. 801–810. https://doi.org/10.1111/j.13652893.2012.01601.xKosi 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.xAlvarez-Uria, G. Long-term outcome of tenofovir disoproxil fumarate use against hepatitis B in an HIV-coinfected cohort / G. Alvarez-Uria, L. Ratcliffe, J. Vilar // HIV Med. – 2009. – Vol. 10, N 5. – P. 269–273. https://doi.org/10.1111/j.14681293.2008.00683.x. 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.xRandomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B / S. Fung [et al.] // Gastroenterology. – 2014. – Vol. 146, N 4. – P. 980–988. e1. https://doi.org/10.1053/j.gastro.2013.12.028Fung 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.2013.12.028Comparative effectiveness of tenofovir in treatment-naïve HIV-infected patients: systematic review and metaanalysis / L. G. Hemkens [et al.] // HIV Clin. Trials. – 2015. – Vol. 16, N 5. – P. 178–189. https://doi.org/10.1179/1945577115Y.0000000004Hemkens 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.0000000004Echenique, I. A. EFV/FTC/TDF-associated hepatotoxicity: a case report and review / I. A. Echenique, J. D. Rich // Aids Patient Care STDs. – 2013. – Vol. 27, N 9. – Р. 493–497. https://doi.org/10.1089/apc.2013.0008Echenique 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.2013.0008Kang, M. K. Tenofovir disoproxil fumarate-induced severe liver injury in a patient with chronic hepatitis B virus infection / M. K. Kang, J. G. Park // Dig. Liver Dis. – 2018. – Vol. 50, N 6. – Р. 628–630. https://doi.org/10.1016/j.dld.2018.03.013Kang 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.2018.03.013Effect of tenofovir, an antiretroviral drug, on hepatic and renal functional indices of Wistar rats: protective role of vitamin E / O. A. Adaramoye [et al.] // J. Basic Clin. Physiol. Pharmacol. – 2012. – Vol. 23, N 2. – Р. 69–75. https://doi.org/10.1515/jbcpp.2011.0042Adaramoye 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.2011.0042Tenofovir disoproxil fumarate: toxicity, toxicokinetics, and toxicogenomics analysis after 13 weeks of oral administration in mice / H. H. Ng [et al.] // Int. J. Toxicol. – 2015. – Vol. 34, N 1. – Р. 4–10. https://doi.org/10.1177/1091581814565669Ng 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/10.1177/1091581814565669Investigating organ toxicity profile of tenofovir and tenofovir nanoparticle on the liver and kidney: experimental animal study / A. I. Peter [et al.] // Toxicol. Res. – 2018. – Vol. 34, N 3. – P. 221–229. https://doi.org/10.5487/TR.2018.34.3.221Peter 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.2018.34.3.221Mitochondrial morphology and dynamics in hepatocytes from normal and ethanol-fed rats / S. Das [et al.] // Pflügers Arch. – 2012. – Vol. 464, N 1. – Р. 101–109. https://doi.org/10.1007/s00424-012-1100-4Das 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/s00424-012-1100-4Mitofusin 2 Protects hepatocyte mitochondrial function from damage induced by GCDCA / Y. Chen [et al.] // PLoS ONE. – 2013. – Vol. 8, N 6. – e65455. https://doi.org/10.1371/journal.pone.0065455Chen 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/s00424-012-1100-4Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence / S.-J. Kim [et al.] // PNAS. – 2014. – Vol. 111, N 17. – Р. 6413–6418. https://doi.org/10.1073/pnas.1321114111Kim 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.1321114111Mitochondrial division ensures the survival of postmitotic neurons by suppressing oxidative damage / Y. Kageyama [et al.] // J. Cell Biol. – 2012. – Vol. 197, N 4. – Р. 535–551. https://doi.org/10.1083/jcb.201110034Kageyama 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

The authors declare that there are no conflicts of interest present.