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IN VITRO EVALUATION OF ALPHA-TOCOPHEROL AS POTENTIAL AGENT IN COMBATING THE HEPATOTOXICITY INDUCED BY ETHINYLESTRADIOL

DAN ILIESCU 1, IASMINA MARCOVICI 2,3*, MONICA SUSAN 1, RAZVAN SUSAN 1, IULIA PINZARU 2,3, RALUCA DUMACHE 1, SORIN CHIRIAC 1

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Drug-induced hepatotoxicity (DIH) represents the main cause of drug withdrawal from therapy. Despite their numerous benefits, oral contraceptives (OCs) present several adverse effects, including a high risk of liver complications. Thus, the main objective of this in vitro study was to assess the potential of alpha-tocopherol (AT) in reducing the cytotoxicity of ethinylestradiol (EE), the primary ingredient of modern OCs, against the HepaRG cell line. The results showed that AT exerted no cytotoxicity in HepaRG cells at the tested concentrations, while EE reduced cell viability and confluence, altered cellular morphology, and induced apoptotic-like nuclear features at 100 µM. These cytotoxic effects were reversed by the co-treatment of EE 100 µM with AT 1 µM - the viability, morphology, and nuclear parameters of the treated cells were similar to those of control cells. However, at 100 µM, AT significantly augmented the hepatotoxicity of EE 100 µM, leading to the highest reduction in cell viability, loss of confluence, fragmentation of cell nuclei, increase of the apoptotic index, and reduction of nuclear area and circumference. Further studies should investigate the hepatoprotective effect of AT at low concentrations against EE-induced liver damage, also considering the potential toxicity resulting from their co-administration in high doses.