Molecular mechanism of nanomaterials induced liver injury: A review

Table 10 Effects and molecular mechanisms underlying iron oxide NPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
Na-oleate coated Fe3O4	8 ± 3 nm (TEM)	Wistar rat	0.0364, 0.364, & 3.64 mg/kg b.w. for 1 d, 1, 2, 4 wks (i.v.)	Temporary change in mitochondrial respiration; GPx, GST (increased); Lipidosis, mild necrosis; Enlarged sinusoid space	[133]
				Oxidative stress
Polyethylene glycol – 8000 coated Fe3O4	8.82 ± 0.70 nm (TEM)	Wistar rat	10 mg/kg b.w. single dose, once in a week, twice in a week for 30 d (i.v.)	ALT, AST, ALP (slightly increased); AST, LPO, SOD, GPx, Neutrophil count (increased); No significant tissue damage	[135]
Fe3O4	20 nm (TEM)	Wistar rat	40 mg/kg b.w. for 14 d (i.t.)	Congestion of sinusoid; Hepatocytic ballooning; Mononuclear cell infiltration; Tissue damage	[132]
				Inflammation
Fe3O4	41.3 ± 5.9 nm for USPIO, 112.6 ± 38.4 nm for SPIO (DLS)	L-02 cells	2.5, 5, 10, and 20 μg/mL) for 12 h	Cell survivility (decreased); Elevated expression of Genes related to acute phase inflammation, ER stress. HSP70, IL-6, PERK, ATF4, ER Ca++ (increased); USPIO show higher toxicity than SPIO	[136]
				ER stress, inflammation
Fe3O4	10 nm (TEM)	Hepatocytes of Lewis rat in sandwich culture model	100, 200, 400 μg/mL, single dose & cumulative dose; 24 h to 7 d	Cell survivility (decreased); ROS (increased); Albumin & urea synthsis (decreased)	[134]
				Oxidative stress
Fe3O4	29.6 ± 12.2 nm (TEM)	Albino wistar rat	30, 300, 1000 mg/kg b.w. for 28 d (nano & bulk) (oral)	GSH, CAT (decreased); SOD, GR, GST, LPO (increased); GPx (unchanged); Congested central vein in higher dose	[130]
				Oxidative stress
Fe2O3	30 nm (TEM)	Wistar rat	100, 200 mg/kg single dose (oral)	ALT (increased) iron deposition in hepatocyte & Kupffer cells	[131]
				Inflammation
Fe2O3	30 nm (TEM)	L-02 cells; BALB/C mice	2.5, 7.5, and 12.5 lg/mL) for 1, 3, 6 h; 20 mg/kg body weight for 24 h. (i.v.)	Cox2 (overexpression); COX-2 interaction with IP3R-GRP75-VDAC1 complex; Ca++ transfer increased; Bax, Cleaved Casp-3 (increased); Bcl2 (decreased)	[137]
				Apoptosis

ALP: Alanine phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Atf4: Activating transcription factor 4; Bax: Bcl-2 associated X protein; Bcl2: B-cell lymphoma 2; Ca++: Calcium ion; CAT: Catalase; COX-2: Cyclooxygenase-2; ER: Endoplasmic reticulum; GPx: Glutathione peroxidase; GR: Glutathione reductase; GRP75: Glucose regulated protein 75; GSH: Glutathione; GST: Glutathione S-transferase; HD: High dose; HSP-70: Heat shock protein 70; IL-6: Interleukin-6; IP3R: Inositol 1,4,5 triphosphate receptor; LD: Low dose; LPO: Lipid peroxidation; PERK: Protein kinase RNA like ER kinase; ROS: Reactive oxygen species; SOD: Super oxide dismutase; SPIO: Superparamagnetic iron oxide; USPIO: Ultra-small superparamagnetic iron oxide; VDAC1: Voltage-dependent anion channel 1; γGT: Gamma glutamyl transferase.