|
| Drug | Modeling methods | Pathology features | Molecular mechanisms |
|
| APAP [10, 11] | Dose: 300-500 mg/kg
Administration: Single i.p., observe 4 hours later | Sinusoidal congestion and hemorrhage, dilated central vein, inflammatory cell infiltration, degenerated hepatocytes showing perinuclear vacuolization | 1. GSH depleted by NAPQI
2. Mitochondrial dysfunction
3. Oxidative stress
4. Activating the protein kinase JNK
5. Hepatocyte apoptosis
6. ER stress and UPR |
|
INH [21, 27]
| 1. Dose: 200 or 400 mg/kg/day
Administration: Gavage daily for one week
2. Dose: INH 75 mg/kg/day and RIF 150 mg/kg/day
Administration: Gavage daily for one week | Hepatocyte steatosis and edema, the sinus almost disappears, part of the mitochondrial cristae disappeared, and the endoplasmic reticulum was vesicular | 1. Mitochondrial injury and dysfunction
2. Hydrazine, the toxic metabolite
3. Apoptosis
4. Oxidative stress
5. Coadministration of RIF induces CYP 450 enzymes and promotes hepatotoxicity
6. Free radical lipid peroxidation |
|
| Tetracycline [34, 37] | 1. Dose: 50 mg/kg
Administration: Single i.p., observe 6 hours later
2. Dose: 200 mg/kg in saline
Administration: Single i.p., observe after 36-hour free diets and 12-hour diet deprivations | Hepatic parenchymal cells microvesicular steatosis, hydropic degeneration around the pericentral zone | 1. Affecting cellular lipid metabolism
2. Apoptosis
3. ER stress
4. Oxidative stress |
|
| CsA [43], | Dose: 20 mg/kg, (Sandimmun infusion dissolved in olive oil, 25mg/ml)
Administration: Subcutaneous injection daily for 21 days | Hepatocyte steatosis, apoptosis, vacuolar degeneration hepatocytes, lipid droplets, reduced mitochondrial cristae, and rough endoplasmic reticulum cystic expansion | 1. Imbalance between production of oxygen free radicals and the endogenous antioxidant defense system
2. Substantial increase in caspase 3 activity that induces apoptosis |
|
| TwHF [54, 55, 59] | 1. Dose: 300 mg/kg TP
Administration: Gavage, observe after 18 hours
2. Dose: 600 μg/kg TP
Administration: Intragastric gavage daily for 5 days
3. Dose: 120 mg/kg GTW
Administration: Gavage daily for 28 days | Extensive hepatocyte turbidity, focal hepatocyte ballooning in the central vein and peripheral areas, scattered eosinophilic changes in hepatocytes
Tendencies toward augmented focal necrosis, inflammatory cell infiltration, and bile duct hyperplasia Partial necrosis with inflammatory cell infiltration in hepatocytes | 1. Cells apoptosis
2. Mitochondria lesions
3. Immune response
4. Lipid peroxidation
5. Inflammation
6. Oxidative stress |
|
PM [67, 73]
| 1. Dose: 2.8 mg/kg LPS with uncertain doses of EA extract of PM
Administration: Tail vein injection of LPS and intragastrically administer EA
extract of PM
2. Dose: 5.4 g/kg water extract of processed PM
Administration: i.p. for 7 days | Hepatocyte focal necrosis, loss of central vein intima and a large number of inflammatory cell infiltration | 1. Disruption of energy metabolism, amino acid and lipid metabolism
2. Inflammatory response
3. Steatosis
4. CYP1A2 and CYP2E1 mRNA expression levels were significantly inhibited |
|
VPA [75, 76]
| Dose: 500 mg/kg/d
Administration: Gavage for 2 weeks | Massive necrosis, liver steatosis and increase of lipid accumulation | 1. Oxidative stress
2. Hepatotoxic metabolites |
|
| CBZ [84] | Dose: 400 mg/kg for 4 days and 800 mg/kg on the 5th day
Administration: Oral gavage
| Prominent hepatic necrosis and loss of hepatocytes,
especially around the central vein
Hepatocytes showed hemorrhage, centrilobular and sinusoidal congestion | 1. The neutralization of IL-17
2. Metabolite(s) indirectly activates TLR4 and RAGE, resulting in inflammation |
|
| Drug/inflammation interaction models | MMI or PTU with LPS [94]
Dose: MMI, 10-50 mg/kg, PTU, 10-50 mg/kg, and LPS, 100 µg/kg
Administration: MMI&PTU: oral, and LPS: i.p. | Inflammatory cells infiltration, intracanalicular cholestasis, fatty changes | 1. Drug reactive metabolite formation and inflammation induction
2. Immunological reactions
3. Oxidative stress |
TVX with LPS [103]
Dose: TVX: 150 mg/kg, LPS: 67×106 EU/ kg
Administration: TVX: oral, and LPS: i.p. | Inflammatory cell infiltration; coagulative necrosis located predominantly midzonally and in centrilobular region | 1. Enhanced TNF release
2. Activation of the hemostatic system
3. Neutrophils accumulation |
SLD with LPS [104]
Dose: SLD: 50 mg/kg, LPS: 8.25 × 105 EU/kg
Administration: SLD: oral; two administrations with a 16-hour interval. LPS: i.v.; half an hour before the second administration of SLD | Midzonal hepatic necrosis |
DCLF with LPS [95]
Dose: DCLF: 20 mg/kg, LPS: 29 × 106 EU/kg
Administration: DCLF: i.p., and LPS: i.v., 2 hours before DCLF | Parenchymal edema (multifocal); parenchymal hemorrhage (multifocal); apoptosis (random); leukocyte infiltration |
RAN with LPS [105]
Dose: RAN: 30mg/kg, LPS: 44.4 × 106 EU/kg
Administration: RAN: i.v., and LPS: i.v., 2 hours before RAN | Acute, multifocal, midzonal hepatic necrosis developed as early as 3 h; hepatocellular cytoplasmic eosinophilia and nuclear pyknosis; variable numbers of infiltrating PMNs |
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