Hepatic impacts of gold nanoparticles with different surface coatings as revealed by assessing the hepatic drug-metabolizing enzyme and lipid homeostasis in mice

Abstract Liver is the major organ in the metabolization of drugs, and detoxification of exogenous substances, including nanoparticles. In clinical medical practice, drug-induced liver injury (DILI) is the major cause of acute liver failure (ALF). In this study, we explore the possible impact of intravenously injected citrate acid (CA), chitosan (CS) and polyethyleneglycol (PEG) functionalized gold nanoparticles (GNPs) on the liver of mice at the doses (60 and 120 μg/mouse) relevant to their biomedical applications. Overall, the results provide the evidence that all the GNPs did not induce obvious liver injury and hepatic steatosis in mice. However, the study highlights that alteration in the function of drug-metabolizing enzymes in the HepaRG cells was associated with the increase cytotoxicity of GNP treatments. Moreover, the deposited GNPs in the liver disturb the expression of drug-metabolizing enzymes, including drug uptake and efflux transporters, and cytochrome P450 (CYP450) isoforms and phase II metabolized enzymes. The mechanism of GNP-induced hepatotoxicity in mice is associated with hyperactivation of mTOR signalling and SREBP-1c-mediated de novo lipogenesis with hepatic inflammation. This also suggests that when using GNPs for biomedical applications, it is necessary to consider the influence of nanomaterial-liver interaction and nanomaterial-induced hepatotoxicity on drug-metabolizing enzymes and lipid homeostasis.