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Introduction: Oxidative stress has been suggested as the main trigger and pathological mechanism of toxic liver injury. Effects of powerful free radical scavenger С60 fullerene on rat liver injury and liver cells (HepG2 line) were aimed to be discovered. Methods: Acute liver injury (ALI) was simulated by single acetaminophen (APAP, 1000 mg/kg) administration, on a chronic CLI, by 4 weekly APAP administrations. Pristine C60 fullerene aqueous colloid solution (C60FAS; initial concentration 0.15 mg/mL) was administered per os or intraperitoneally at a dose of 0.5 mg/kg (ALI) or 0.25 mg/kg (CLI) daily for 2 or 28 days, respectively, after first APAP dose. Animals were sacrificed at 24th hour after the last dose. Biochemical markers of blood serum and liver autopsies were analyzed. EGFR expression in HepG2 cells after 48-hour incubation with C60FAS was assessed. Results: Increase of serum conjugated and unconjugated bilirubin (up to 1.4-3.7 times), ALT (by 31-37%), and AST (by 18%) in non-treated ALI and CLI rats were observed, suggesting the hepatitis (confirmed by histological analysis). Liver morphological state (ALI, CLI), ALT (ALI and CLI), bilirubin (CLI), α-amylase, and creatinine (ALI) were normalized with C60FAS administration in both ways, which may indicate its protective impact on liver. However, unconjugated bilirubin sharply increased in ALI animals receiving C60FAS (up to 12 times compared to control), suggesting the augmentation of bilirubin metabolism. Furthermore, C60FAS inhibited EGFR expression in HepG2 cells in a dose-dependent manner. Conclusion: C60FAS could partially correct acute and chronic toxic liver injury, however, it could not normalize bilirubin metabolism after acute exposure.

Liver cirrhosis is an outcome of a wide range of liver chronic diseases. It is attributed to oxidative stress; therefore, antioxidant usage could be a promising treatment of that. So, exploring the impact of effective free radical scavenger pristine C60 fullerenes on liver fibrosis and cirrhosis and their ability to interact with main growth factor receptors involved in liver fibrogenesis was aimed to be discovered. We used N-diethylnitrosamine/carbon tetrachloride-induced simulations of rat liver fibrosis (10 weeks) and cirrhosis (15 weeks). Pristine C60 fullerene aqueous colloid solution (C60FAS) was injected daily at a dose of 0.25 mg/kg throughout the experiment. Liver morphology and functional and redox states were assessed. C60 fullerenes’ ability to interact with epidermal, vasoendothelial, platelet-derived, and fibroblast growth factor receptors (EGFR, VEGFR, PDGFR, and FGFR, respectively) was estimated by computational modeling. We observed that C60FAS reduced the severity of fibrosis in fibrotic rats (0.75 vs. 3.0 points according to Ishak score), attenuated the hepatocyte injury, normalized elevated blood serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), and mitigated oxidative stress manifestation in liver tissue restoring its redox balance. When applied to cirrhotic animals, C60FAS reduced connective tissue deposition as well (2.4 vs. 5.4 points according to Ishak score), diminished ALP and LDH (by 16% and 61%), and normalized conjugated and nonconjugated bilirubin, restoring the liver function. Altered liver lipid and protein peroxides and glutathione peroxidase activity were also leveled. Within a computer simulation, it was shown that C60 fullerenes can block hinge prohibiting ATP binding for EGFR and FGFR and thus blocking associated signal pathways. This ability in addition to their antioxidant properties may contribute to C60 fullerene’s antifibrotic action. Thus, C60FAS may have a substantial therapeutic potential as an inhibitor of liver fibrosis and cirrhosis.