nogrЭкспериментальная и клиническая гастроэнтерологияExperimental and Clinical Gastroenterology1682-8658«Global Media Technologies»10.31146/1682-8658-ecg-206-10-70-76nogr-2161Research ArticleЭКСПЕРИМЕНТАЛЬНАЯ ГАСТРОЭНТЕРОЛОГИЯEXPERIMENTAL GASTROENTEROLOGYЛиния клеток HepG2 как модель для изучения проникновения статинов в гепатоцитыHepG2 cell line as a model for studying of the statins’ hepatic uptakehttps://orcid.org/0000-0003-4802-5656ЕрохинаП. Д.ErokhinaP. D.noemail@neicon.ruhttps://orcid.org/0000-0003-0696-6554СлепневА. А.SlepnevA. A.noemail@neicon.ruhttps://orcid.org/0000-0001-7829-2494МыльниковП. Ю.MylnikovP. Yu.noemail@neicon.ruhttps://orcid.org/0000-0002-4408-6454ГанинаС. О.GaninaS. O.noemail@neicon.ruhttps://orcid.org/0000-0002-9025-130XКоняхинЕ. А.KonyakhinE. A.noemail@neicon.ruhttps://orcid.org/0000-0003-1688-0017ЩулькинА. В.ShchulkinA. V.alekseyshulkin@rambler.ruhttps://orcid.org/0000-0001-6887-4888ЯкушеваЕ. Н.YakushevaE. N.noemail@neicon.ruФедеральное государственное бюджетное образовательное учреждение высшего образования Рязанский государственный медицинский университет имени академика И. П. Павлова Министерства здравоохранения Российской ФедерацииРоссияRyazan State Medical UniversityRussian Federation2022180120230107076Copyright © Ерохина П.Д., Слепнев А.А., Мыльников П.Ю., Ганина С.О., Коняхин Е.А., Щулькин А.В., Якушева Е.Н., 20232023Ерохина П.Д., Слепнев А.А., Мыльников П.Ю., Ганина С.О., Коняхин Е.А., Щулькин А.В., Якушева Е.Н.Erokhina P.D., Slepnev A.A., Mylnikov P.Y., Ganina S.O., Konyakhin E.A., Shchulkin A.V., Yakusheva E.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.nogr.org/jour/article/view/2161

Статины (ингибиторы β-гидрокси-β-метил-глутарил-КоА редуктазы) - основной класс препаратов для лечения дислипидемий. Для повышения безопасности терапии при их использовании необходима тест-система для оценки их проникновения в гепатоциты с помощью белков-транспортеров ОАТР1В1/ОАТР1В3. Цель исследования разработать метод оценки проникновения статинов внутрь гепатоцитов на клетках линии HepG2 (гепатоцеллюлярная карцинома человека). Материалы и методы. Клетки культивировали в 6- и 24 луночных планшетах. Наличие ОАТР1В1 в клетках линии HepG2 оценивали с помощью метода вестерн-блот. Проникновение статинов в клетки анализировали на примере аторвастатина. Его добавляли к монослою клеток в концентрациях 1 и 10 мкМ и инкубировали в течение 30 минут. Затем клетки снимали с лунок, лизировали различными способами и определяли количество аторвастатина методом высокоэффективной жидкостной хроматографии с тандемным масс-селективным детектированием (ВЭЖХ-МС/МС). Результаты исследования. Методом вестерн-блот было показано наличие ОАТР1В1 в клетках линии HepG2, основного белка, транспортирующего статины внутрь гепатоцитов. Наилучшим способом лизиса клеток оказался трехкратный цикл «заморозка-разморозка» при -80 °C. Аналитический диапазон методики количественного определения аторвастатина в лизате клеток HepG2 методом ВЭЖХ-МС/МС составил 0,5-200 нмоль/л, что позволило выполнять транспортные эксперименты при добавлении аторвастатина в концентрации 1 мкМ и инкубации в течение до 30 мин. Применение ингибитора ОАТР1В1/ ОАТР1В3 - рифампицина (100 мкМ) снижало проникновение аторвастатина внутрь клеток HepG2, что подтверждает адекватность предложенного метода. Выводы. Разработана методика оценки проникновения статинов в гепатоциты на клетках линии HepG2.

Statins (β-hydroxy-β-methyl-glutaryl-CoA reductase inhibitors) are the main class of drugs for the treatment of dyslipidemia. To improve the safety of therapy with their use, a test system is needed to assess their penetration into hepatocytes using OATP1B1/OATP1B3 transporter proteins. The aim of the study was to develop a method for assessing the penetration of statins into hepatocytes on HepG2 cells (human hepatocellular carcinoma). Materials and methods. Cells were cultured in 6- and 24-well plates. The presence of OATP1B1 in HepG2 cells was assessed using the Western blot method. Penetration of statins into cells was analyzed using atorvastatin as an example. It was added to the cell monolayer at concentrations of 1 and 10 μM and incubated for 30 minutes. The cells were then removed from the wells, lysed in various ways, and the amount of atorvastatin was determined by high performance liquid chromatography with tandem mass selective detection (HPLC-MS/MS). Results. Western blot showed the presence of OATP1B1 in HepG2 cells, the main protein that transports statins into hepatocytes. The best way to lyse the cells was a three-cycle freeze-thaw cycle at -80 °C. The analytical range of the method for the quantitative determination of atorvastatin in the lysate of HepG2 cells by HPLC-MS/MS was 0.5-200 nmol/l, which made it possible to perform transport experiments with the addition of atorvastatin at a concentration of 1 μM and incubation for up to 30 min. The use of the OATP1B1/OATP1B3 inhibitor rifampicin (100 μM) reduced the penetration of atorvastatin into HepG2 cells, which confirms the adequacy of the proposed method. Conclusions. A technique for assessing the penetration of statins into hepatocytes on HepG2 cells has been developed.

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