Molecular mechanism of nanomaterials induced liver injury: A review

Table 12 Effects and molecular mechanisms underlying carbon nanotube induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
MWCNTs	O-MWCNT; T-MWCNT; Length 356 ± 185 nm	Kunming mice	10 and 60 mg/kg b.w. (Iv) sacrificed at 15 & 60 d	GSH, SOD (decreased at 15 days); AST, T-Bil (increased); Spotty necrosis, Infiltration of inflammatory cells in portal region, mitochondrial swelling and lysis; Cyp2B19 (upregulated); Cyp2C50, Gsta2 (downregulated)	[149]
				Oxidative stress, Inflammation
PEGylated; MWCNT	P- MWCNT; NP- MWCNT; Length of less than 1 μm; Diameter of 10-20 nm	Kunming mice	10 and 60 mg/kg b.w. (Iv) sacrificed at 15 & 60 d	Blackish discoloration of the liver (MWCNTs accumulation); AST, Bag4, Gab1 genes (increased); Infiltration inflammatory cells, cellular necrosis, focal necrosis; Mitochondrial swelling/lysis; NP- MWCNT shows more toxicity than P- MWCNT	[155]
				Inflammation
Carboxylated functionalized SWCNT	lengths of 15–20 μm; Diameter of 15–30 nm	Swiss webster mice	0.25, 0.5 & 0.75 mg/kg b.w. per day for 5 d (Ip)	ROS, LHP, ALT, AST, ALP, (increased); Histological alterations	[153]
				Oxidative stress
Carboxylated functionalized; MWCNTs	lengths of 15–20 μm; Diameter of 15–30 nm	Swiss webster mice	0.25, 0.5 & 0.75 mg/kg b.w. per day for 5 d (Ip)	ROS, LHP, ALT, AST, ALP, (increased); Histological alterations	[154]
				Oxidative stress
MWCNTs	Length 5-50 μm; Diameter 20-30 nm (SEM)	Swiss albino mice	10 and 60 mg/kg b.w. (oral) sacrificed at 7, 14, 21, 28 d	SOD, CAT activity (decreased); Macrophage injury, cellular swelling, unspecific inflammation, spot necrosis, blood coagulation. The sinusoid and hepaticvenule diameter increased by the high dose	[156]
				Oxidative stress
SWCNTs	Length several μm; Diameter 0.8-1.2 nm (TEM)	Wistar rat	7.5 (low), 15 (medium), and 22.5 (high) mg/kg b. w. Intratracheal instillation once for 15 d	ALB, ALP, TP, TC (decreased at high conc.); Focal necrosis, inflammatory cell infiltration, Cellular swelling at centrilobular part, membrane fluidity destruction, impaired amino acid & lipid metabolism	[150]
				Metabolic disruption, Hepatotoxicity
Oxidised MWCNTs	Length 1-2 μm; Diameter 10-30 nm (TEM)	Kunming mice (Cd-MT accumulated mice)	500 μg/mouse for 4 h	ALT, AST, TBil, BUN (increased); Released Cd++ from Cd-MT; Adsorb a part of free Cd++	[157]
				Coexpossure ameliorated hepatotoxicity
Carboxylated MWCNTs	Length 12 μm; Diameter 11.5 nm (TEM)	Wistar rat	0.25, 0.50, 0.75 and 1.0 mg/kg b.w. for 5 consecutive days (Ip)	ALT, AST, ALP, GGT (increased); LPO, H2O2, CAT, GPx, activity (increased); SOD, GST (decreased); IL-6, IL-1β, COX-1, iNOS, TNF-α (increased); micronucleated polychromatic erythrocytes (MNPCE)	[151]
				Oxidative stress, Inflammation
MWCNTs	Polycrystalline; Length 600-700 nm; Size 650 nm	Albino rat	1 g/kg b. w. (oral) 4 wk	LPO, H2O2, TT, CATactivity (increased); SOD, GSH, GPx, GST (decreased); IL-6, IL-1β, COX-1, TNF-α (increased); hydropic degeneration focal hepatic & perivascular hepatic necrosis associated with inflammatory cells, infiltration, sinusoidal leukocytosis, vacuolar degeneration, congestion of central vein	[4]
				Oxidative stress, Inflammation
Carboxylated MWCNTs	diameter: 5–15 nm, length: 0.5-2 μm (TEM)	C57BL/6J mice (NAFLD)	MWCNT; LD-10 mg/kg b.w. HD-30 mg/kg b.w. PbAc LD-150 mg/kg b.w. HD-300 mg/kg b.w. MWCNT+ PbAc, LD-10 mg/kg +150 mg/kg HD-30 mg/kg +300 mg/kg (Intragastrically) daily for 80 d	Death at high dose on 5th day. ALT, AST, ALP (decreased); Nonalcoholic steatohepatitis lobular inflammation, hepatic fibrosis, steatosis, apoptotic induction in primary hepatocytes of NAFLD mice; SOD, GST, GSH (decreased); H2O2, GPx, MDA, LPO (increased); Lipid peroxidation; IL-6, IL-1β and TNF-α (inflammatory cytokines) inhibiting AMPK/PPARγ pathway	[152]
				Oxidative stress, Inflammation

ALB: Albumin; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AMPK: AMP activated protein kinase; AST: Aspartate aminotransferase; Bag4: BAG cochaperone 4; BUN: Blood urea nitrogen; CAT: Catalase; COX-1,2: Cyclooxygenase-1,2; Cyp2B19: Cytochrome P4502B19; Cyp2C50: Cytochrome P4502C50; Gab1: GRB2 associated binding protein 1; GGT: Gamma glutamyl transferase; GPx: Glutathione peroxidase; GSH: Glutathione; Gsta2: Glutathione S-transferase, alpha2; GST: Glutathione-S transferase; H₂O₂: Hydrogen peroxide; IL-1β: Interleukin-1beta; IL-6: Interleukin-6; iNOS: Inducible nitric oxide synthase; LHP: Lipid hydroperoxide; LPO: Lipid peroxidation; MDA: Malondialdehyde; NAFLD: Non-alcoholic fatty liver disease; O-MWCNT-acid: Oxidized multi-walled CNTs; PPARγ: Peroxisome proliferator-activated receptor-γ; ROS: Reactive oxygen species; SOD: Superoxide dismutase; TBil: Total bilirubin; TC: Total cholesterol; T-MWCNT: Tween-80-dispersed multi-walled CNTs; TNF-α: Tumor necrosis factor alpha; TP: Total protein; TT: Total thiol.