Size- and time-dependent alteration in metabolic activities of human hepatic cytochrome P450 isozymes by gold nanoparticles via microsomal coincubations

摘要: Nano-sized particles are known to interfere with drug-metabolizing cytochrome P450 (CYP) enzymes, which can be anticipated a potential source of unintended adverse reactions, but the mechanisms underlying inhibition still not well understood. Herein we report systematic investigation impacts gold nanoparticles (AuNPs) on five major CYP isozymes under in vitro incubations human liver microsomes (HLMs) tannic acid (TA)-stabilized AuNPs size range 5 100 nm. It is found that smaller show more pronounced inhibitory effects CYP2C9, CYP2C19, CYP2D6, and CYP3A4 dose-dependent manner, while 1A2 least susceptible AuNP inhibition. The size- CYP-specific nonspecific drug-nanogold binding coincubation media significantly reduced by increasing concentration ratio microsomal proteins AuNPs, probably via noncompetitive mode. Remarkably, also exhibit slow time-dependent inactivation 2D6 3A4 β-nicotinamide adenine dinucleotide 2′-phosphate tetrasodium salt hydrate (NADPH)-independent manner. During incubations, UV–vis spectroscopy, dynamic light scattering, zeta-potential measurements were used monitor changes particle properties miscellaneous AuNP/HLM/CYP dispersion system. An improved stability mixing HLM nanocolloid reveals stabilization AuNP-HLM interactions may occur faster time scale than salt-induced nanoaggregation incubation phosphate buffer. results suggest induced partially attributed its adhesion onto enzymes alter their structural conformations or membrane therefore impairing integral proteins. Additionally, likely block substrate pocket surface, depending both characteristics diversity isozymes. These findings represent additional for differential arising from coincubated metabolic activities hepatic