Investigation of propofol, fentanyl, and midazolam-related toxicity and the protective effect of midazolam on THLE-2 cell lines

Abstract Objectives The widespread use of propofol, fentanyl, and midazolam in intensive care units necessitates a thorough understanding of their potential toxic effects. These sedative-hypnotic agents are frequently administered in combination to manage critically ill patients, raising concerns about their cumulative toxicity. To address this, we investigated the cytotoxic and genotoxic effects of these drugs, both individually and in combination, on a human liver epithelial cell line (THLE-2). The liver, as a major organ involved in drug metabolism, is particularly vulnerable to drug-induced toxicity. By evaluating the impact of these agents on liver cells, we aim to gain insights into their potential adverse effects and inform clinical practice. Methods Cells were treated with increasing concentrations of each drug, as well as with their combination, over a 72 h incubation period. Cell viability, oxidative stress, antioxidant defense mechanisms and apoptotic activity and potential genotoxicity were explored using various assays. Results A dose dependent increase in cytotoxicity, intracellular reactive oxygen species production, apoptotic activity, and DNA damage were detected in all treatment groups (p<0.05). Higher concentrations of the study drugs were associated with marked increases in oxidative stress and apoptotic markers. There was a concomitant reduction in intracellular glutathione levels, suggesting a depletion of the cells’ antioxidant defenses. When these drugs were administered in combination, the cytotoxic and genotoxic effects appeared to be mitigated, indicating a potential protective interaction between these agents, particularly involving midazolam. Conclusions The study drugs caused dose-dependent hepatotoxicity, induced DNA damage and apoptosis and consequently decreased cell viability.