Assessment of Gold Nanoparticles-Inhibited Cytochrome P450 3A4 Activity and Molecular Mechanisms Underlying Its Cellular Toxicity in Human Hepatocellular Carcinoma Cell Line C3A.

Interactions of the 40 and 80 nm gold nanoparticles (AuNP) functionalized with cationic branched polyethylenimine (BPEI), anionic lipoic acid (LA), or neutral polyethylene glycol (PEG) with human hepatocellular carcinoma (HCC) cell line C3A have been investigated in the absence and presence of human plasma protein corona (PC). All bare (no PC) AuNP besides 80 nm LA-AuNP were cytotoxic to C3A but PC attenuated their cytotoxicities. Time-dependent cellular uptake of AuNP increased besides 40 nm BPEI-AuNP but PC suppressed their uptakes besides 80 nm PEG-AuNP. Biphasic responses of oxidative/nitrosative stress by BPEI-AuNP occurred in C3A cells, whereas PEG-AuNP was a potent antioxidant. All bare AuNP inhibited cytochrome P450 (CYP) 3A4 activity irrespective of size and surface charge but PC recuperated its activity besides PEG-AuNP. The 40 nm PEG-AuNP-modulated gene expression was mainly involved in mitochondrial fatty acid β-oxidation and to a less degree hepatic efflux/uptake transporters. These studies contribute to a better understanding of AuNP interaction with key biological processes and their underlying molecular mechanisms in HCC, which may be further implicated in the development of more effective therapeutic target in HCC treatment.