Оценка лекарственной гепатотоксичности in vitro на клеточных моделях (обзор)

Лекарственная гепатотоксичность составляет 15–18% от общего числа всех причин отзыва лекарственных препаратов из оборота при пострегистрационном применении. Стандартные доклинические исследования in vivo на лабораторных животных часто бывают нерелевантны из-за видоспецифичных различий с человеком. Перспективной альтернативой является разработка методов доклинических исследований in vitro на клеточных культурах.

Цель работы — обзор современных клеточных моделей для определения лекарственной гепатотоксичности in vitro.

Клетки, используемые для изучения механизмов гепатотоксичности in vitro, должны обладать специфичным метаболизмом и активностью ферментных и транспортных систем печени. Представлен обзор по основным клеточным культурам (первичные гепатоциты, бессмертные клеточные линии, гепатоцит-подобные клетки, полученные из стволовых клеток, и сокультуры из гепатоцитов и непаренхиматозных клеток) и конфигурациям клеточных систем. Продемонстрировано, что совершенствование клеточных систем происходит в направлении увеличения продолжительности жизни и функциональной сохранности клеток, усложнения конфигурации и клеточного состава с приближением к условиям in vivo. Установлено, что лекарственное повреждение печени может происходить вследствие образования химически активных метаболитов, развития оксидативного стресса, митохондриального повреждения, внутриклеточного накопления токсических желчных кислот при ингибировании транспортеров, активации адаптивной иммунной системы. В связи с этим для исследования лекарственной гепатотоксичности применяют различные методики, в том числе инновационные технологии (одновременного многопараметрического скрининга, транскриптомики, протеомики, метаболомики) для получения, хранения и обработки большого объема данных. Клеточные модели могут использоваться не только для выявления лекарственной гепатотоксичности, но и для изучения механизмов повреждения печени. Наиболее перспективными являются омик-технологии, создание сложных моделей с сокультивированием различных типов клеток и органы-на-чипе.

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