Abstract Scopolamine (SCO) is an anticholinergic drug widely prescribed for motion sickness and gastrointestinal disorders; however, its dose-dependent toxicity has been increasingly linked to mitochondrial dysfunction. Despite its long-standing clinical use, the mechanistic basis of SCO-induced cytotoxicity remains poorly characterized. HepG2 cells were cultured in either high-glucose or galactose media to modulate mitochondrial dependence. Cell viability and adenosine triphosphate (ATP) levels were then measured to evaluate mitochondrial function and integrity following SCO exposure. Complementary in silico molecular docking, molecular dynamics simulations, and binding energy analyses were performed to predict potential mitochondrial protein targets and explore the stability of SCO-protein interactions. SCO caused more pronounced cytotoxicity and ATP depletion in galactose-adapted HepG2 cells, suggesting the involvement of mitochondrial mechanisms. At 6000 μM, SCO reduced ATP levels by 98% in galactose medium compared to 35% in high-glucose medium. Computational analyses suggested plausible interactions with voltage-dependent anion-selective channel 1 (VDAC1), complex I, and adenine nucleotide translocator (ANT). This study provides preliminary mechanistic insight indicating that SCO exerts its cytotoxic effects primarily through mitochondrial pathways. The in silico analyses constitute the first predictive assessment of SCO’s potential mitochondrial targets, particularly complex I, VDAC1, and ANT, which may inform future experimental validation. Overall, our findings propose that mitochondrial involvement plays a significant role in SCO-induced cytotoxicity and emphasize the value of integrating experimental and computational approaches to advance mechanistic toxicology and drug safety evaluation.
Ergüç et al. (Sat,) studied this question.