Table 1.
Summary of DILI compound modulation of Nrf2 and NF-κB signaling and onset of DILI compound/TNFα cytotoxic synergy
| Drug name | Abbreviation | Function | DILI label/score | DILI classification | DILI type | DILI concern | Nrf2 response assay (fold induction) | NF-κB oscillation delay upon TNFα | Apoptosis assay (+last 16 h TNFα) | Apoptosis effect of TNFα (% increase) | Nrf2 transcripts up and NF-κB transcripts down |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Troglitazone | TGZ | Antidiabetic | N.A. | N.A. | Acute—cholestatic injury | Most | 1.3× | 2 min | 1.1 % (2.6 %) | 1.5 | N.A |
| Isoniazid | INH | Antimycobacterial drug | B.W. 8 | Fatal hepatotoxicity | Acute—hepatocellular injury | Most | 1.0× | 2 min | 2.8 % (3.3 %) | 0.5 | 2–9 |
| Ofloxacin | OFX | Antibiotic | N.A. | N.A. | Acute—hepatocellular injury | Less | 1.1× | 8 min | 2.3 % (3.2 %) | 0.9 | N.A |
| Simvastatin | SN | Antihyperlipidemic | W/P 3 | Liver aminotransferases increase | Acute—hepatocellular injury | Less | 1.1× | 2 min | 2.5 % (3.6 %) | 1.1 | 2–19 |
| Naproxen | NPX | NSAID | W/P 3 | Liver aminotransferases increase | Acute—cholestatic injury | Less | 1.8× | 4 min | 2.1 % (2.3 %) | 0.2 | 2–4 |
| Methotrexate | MTX | Antineoplastic agent | B.W. 3 | Liver aminotransferases increase | Chronic—microvesicular steatosis | Less | 3.3× | 9 min | 1.9 % (1.9 %) | 0 | N.A |
| Amiodarone | AMI | Antiarrhythmic agent | B.W. 8 | Fatal hepatotoxicity | Chronic—steatohepatitis | Most | 1.9× | 22 min | 5.8 % (9.0 %) | 3.2 | 0–0 |
| Acetaminophen | APAP | Analgesic and antipyretic | W/P 5 | Jaundice | Acute—hepatocellular injury | Most | 4.0× | 4 min | 2.5 % (2.5 %) | 0 | 12–29 |
| 3′-Hydroxyacetanilide | AMAP | Regioisomer of paracetamol | N.A. | N.A. | N.A. | Less | 4.0× | 4 min | 3.1 % (3.4 %) | 0.3 | N.A |
| Nitrofurantoin | NTF | Antibacterial | W/P 8 | Fatal hepatotoxicity | Chronic—autoimmune hepatitis | Most | 4.6× | 29 min | 2.9 % (3.6 %) | 0.7 | 15–23 |
| Nefazodone | NFZ | Antidepressant | B.W. 8 | Fatal hepatotoxicity | Acute—hepatocellular injury | Most | 4.8× | 22 min | 3.5 % (6.8 %) | 3.3 | 13–20 |
| Clozapine | CLZ | Antipsychotic drug | W/P 25 | Cholestasis; steatohepatitis | Acute—cholestatic injury | Most | 4.6× | 12 min | 4.0 % (7.7 %) | 3.7 | 1–12 |
| Carbamazepine | CBZ | Antiepileptic drug | W/P 7 | Acute Liver Failure | Acute—cholestatic injury | Most | 4.1× | 20 min | 3.9 % (22.5 %) | 18.6 | 4–9 |
| Diclofenac | DCF | NSAID | W/P 8 | Fatal hepatotoxicity | Acute—hepatocellular injury | Most | 6.7× | 26 min | 4.5 % (14.2 %) | 9.7 | 12–23 |
| Ketoconazole | KTZ | Antifungal antibiotic | B.W. 8 | Fatal hepatotoxicity | Acute—hepatocellular injury | Most | 8.3× | 26 min | 5.0 % (8.1 %) | 3.1 | 9–17 |
Full names, abbreviations and function of the drugs chosen for this study. The DILI classification was derived from Chen et al. (2011). The overall results from the current study are summarized as fold induction of the Srxn1-GFP intensity compared to control (Nrf2 response), timing of the GFP-p65 assay, focusing on the delay in the second nuclear translocation event upon TNFα exposure (NF-κB response) and percentage of dead cells as observed by the Annexin-V live assay (including TNFα-enhanced cell death)