Table 3.
Cytotoxic effects of the tested compounds in hiPSC derived hepatocytes (hiPS-HEP) and HepG2: minimal effective concentration and toxicity risk steatotic risk index.
| Cell system | Compound | Fixed assay | Live assay | C max a | TRb | SRIc | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| V | NC | S | PL | V | NC | MMP | ROS | PMP | Lipid | ROS | ||||||||||
| CC | MI | A | C | MI | A | C | MI | A | CC | MI | A | MI | MI | MI | ||||||
| hiPS-HEP | AMD | 39.5 | 39.5 | — | 39.5 | 125 | 39.5 | 12.5 | 12.5 | 12.5 | 39.5 | 39.5 | — | 39.5 | 39.5 | 125 | 2.2 | 5.7 | 18 | 18 |
| DOX | 100 | — | 316 | 316 | 1000 | — | — | — | — | 1000 | 100 | 100 | 1000 | — | 31.6 | 8.8 | 3.6 | 36 | >114 | |
| TET | 1000 | — | 316 | 316 | 1000 | — | — | — | — | 1000 | — | 316 | — | 316 | — | 14.2 | 22.3 | 22 | 22 | |
| SC | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | NA | NA | NA | NA | |
|
| ||||||||||||||||||||
| HepG2 | AMD | 4 | 39.5 | 125 | 39.5 | 39.5 | 125 | — | — | — | 12.5 | 39.5 | 39.5 | 12.5 | 12.5 | 125 | 2.2 | 1.8 | 18 | 6 |
| DOX | 100 | 1000 | 1000 | 316 | 1000 | — | — | — | — | 316 | — | — | 1000 | 316 | 1000 | 8.8 | 11.4 | 36 | 36 | |
| TET | 316 | 100 | 316 | 100 | 100 | — | — | 100 | — | — | 1000 | 316 | — | 1000 | 1000 | 14.2 | 7.0 | 7 | 70 | |
| SC | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | NA | NA | NA | NA | |
Mechanism affected at the lowest concentration is denoted in bold. Statistical significance was performed using one-way ANOVA followed by Dunnett's test. AMD: amiodarone HCl; DOX: doxycycline; TET: tetracycline; V: viability; NC: nuclear changes; S: steatosis; PL: phospholipidosis; MMP: mitochondrial membrane potential; ROS: reactive oxygen species; PMP: plasma membrane permeability; CC: cell count; MI: mean intensity; A: area; C: droplet count. aMaximum plasma concentration of the drug (C max), bThe toxicity risk (TR) for each compound was defined as ratio of minimal effective concentration to the maximum plasma concentration of the drug (C max). cSteatotic risk index (SRI) was calculated as the ratio of the MEC for neutral lipid accumulation or for ROS generation to the C max.