Hepatotoxicity assessment of antimalarial compounds from microorganisms using a liver organ-on-a-chip system

The emergence of drug-resistant malaria strains in sub-Saharan Africa and Southeast Asia has spurred the search for novel antimalarial compounds. Microorganisms yield diverse secondary metabolites that possess strong biological activities. To assess the safety of these potential drugs, particularly in relation to liver toxicity, researchers evaluated three antimalarial candidates using a liver organ-on-a-chip (OOC) system.

The compounds tested were thiolutin (NATPP0650), cochliodinol (NATPP0437), and 4-hydroxy-mycophenolic acid (NATPP0604). Both NATPP0650 and NATPP0437 exhibited significant acute toxicity at concentrations of 10 and 50 µM in HepG2 cells, while NATPP0604 showed relatively low toxicity. The OOC system revealed that NATPP0650 and NATPP0437 had a computed CC50 (the concentration causing 50% cytotoxicity) of 3.04 and 2.21 µM, respectively, while NATPP0604 had a higher CC50 of 50 µM, indicating better safety and a selectivity index exceeding 23.7.

Functional tests on HepG2 cells in the OOC system showed that NATPP0650 and NATPP0437 significantly reduced albumin production at 10 and 50 µM, whereas NATPP0604 had minimal inhibition. However, long-term exposure testing over 7 days in the OOC model revealed unexpected delayed hepatotoxic effects for NATPP0604, with partial cell viability reductions and decreased albumin production even at lower concentrations (10 and 50 µM).

This study underscores the need to consider long-term hepatotoxicity assessments in the safety evaluation of antimalarial drugs derived from microorganisms before advancing to clinical trials.