Chemistry and Biochemistry: Research Progress Vol. 12

Preclinical safety profiling refers to the assessment of the potential toxic effects of compounds in vitro before progression to clinical trials. This evaluation typically includes parameters such as cytotoxicity, neurotoxicity, and cardiotoxicity. Curcumin (CUR), atractylodin (ATD), α-mangostin (αMG), ethyl-p-methoxycinnamate (EPMC), ligustilide (LIG), and β-eudesmol (BEU) are prominent bioactive compounds frequently used in Thai traditional medicine formulations. This study evaluated the cytotoxic profiles of these natural compounds in HepG2 hepatocellular carcinoma cells and ReNcell VM neural progenitor cells using the resazurin reduction assay. In addition, their potential to induce cardiotoxicity through hERG channel inhibition was assessed in hERG-overexpressing HEK293 cells using automated patch-clamp electrophysiology. The results indicated that αMG and CUR significantly reduced HepG2 cell viability (IC50 values of 5.5 µM and 21 µM, respectively), with reductions of 75% and 50% in total cell viability, respectively. In undifferentiated ReNcell VM cells, αMG emerged as the most potent inhibitor of viability (IC₅₀ = 2.1 µM), followed by CUR (IC₅₀ = 21.1 µM), resulting in decreases in viability of approximately 80% and 50%, respectively. However, in differentiated ReNcell VM populations, only αMG demonstrated significant neurotoxicity (IC₅₀ = 6.0 µM). The remaining compounds exerted no substantial cytotoxic effects on these cell lines. Regarding cardiotoxicity, ATD, BEU, LIG, and EPMC exhibited low inhibition of hERG channels (IC₅₀ = 26.4, 33.4, 37.3, and 53 µM, respectively), whereas CUR and αMG displayed negligible inhibitory effects (IC₅₀ > 100 µM). These findings suggest that, while αMG may exert cytotoxic effects on hepatocytes and neurons at concentrations far exceeding standard dietary or medicinal intake, compounds such as ATD, BEU, EPMC, LIG, and CUR are unlikely to cause significant adverse effects at typical clinical doses. Nonetheless, if these phytochemicals are advanced in drug development, their hERG interaction profiles warrant careful monitoring to mitigate cardiotoxic risks. Comprehensive preclinical and clinical pharmacokinetic evaluations are essential to elucidate the relationships between the in vivo plasma concentration profiles of compounds such as EPMC and their respective thresholds for hepatotoxicity, neurotoxicity, cardiotoxicity, and drug-drug interactions.

Abstract Curcumin (CUR), atractylodin (ATD), α-mangostin (αMG), ethyl-p-methoxycinnamate (EPMC), ligustilide (LIG), and β-eudesmol (BEU) are prominent bioactive compounds frequently used in Thai traditional medicine formulations. This study evaluated the cytotoxic profiles of these natural compounds in HepG2 hepatocellular carcinoma cells and ReNcell VM neural progenitor cells using the resazurin reduction assay. In addition, their potential to induce cardiotoxicity through hERG channel inhibition was assessed in hERG-overexpressing HEK293 cells using automated patch-clamp electrophysiology. The results indicated that αMG and CUR significantly reduced HepG2 cell viability (IC₅₀ values of 5.5 µM and 21 µM, respectively), with reductions of 75% and 50% in total cell viability, respectively. In undifferentiated ReNcell VM cells, αMG emerged as the most potent inhibitor of viability (IC₅₀ = 2.1 µM), followed by CUR (IC₅₀ = 21.1 µM), resulting in decreases in viability of approximately 80% and 50%, respectively. However, in differentiated ReNcell VM populations, only αMG demonstrated significant neurotoxicity (IC₅₀ = 6.0 µM). The remaining compounds exerted no substantial cytotoxic effects on these cell lines. Regarding cardiotoxicity, ATD, BEU, LIG, and EPMC exhibited low inhibition of hERG channels (IC₅₀ = 26.4, 33.4, 37.3, and 53 µM, respectively), whereas CUR and αMG displayed negligible inhibitory effects (IC₅₀ > 100 µM). These findings suggest that, while αMG may exert cytotoxic effects on hepatocytes and neurons at concentrations far exceeding standard dietary or medicinal intake, compounds such as ATD, BEU, EPMC, LIG, and CUR are unlikely to cause significant adverse effects at typical clinical doses. Nonetheless, if these phytochemicals are advanced in drug development, their hERG interaction profiles warrant careful monitoring to mitigate cardiotoxic risks. Comprehensive preclinical and clinical pharmacokinetic evaluations are essential to elucidate the relationships between the in vivo plasma concentration profiles of compounds such as EPMC and their respective thresholds for hepatotoxicity, neurotoxicity, cardiotoxicity, and drug-drug interactions.