Nanosilver Particle Effects on Drug Metabolism In Vitro

Nano-silver particles are present in consumer and health care products. Their effects on human microsomal cytochrome P450 activities and induction in luciferase reporter-engineered Caco-2 (MDR1.C) and HepG2 (DPX2 and 1A2DRE) cells have been investigated. The LD50 was ~4 μg silver/ml for HepG2 and 5 μg/ml for Caco-2 cells. At silver concentrations showing no viability decrease (<1 μg silver/ml), the PXR-driven 4.5-fold induction response of MDR1.C cells to 50 μM omeprazole was unaffected. In DPX2 cells, the PXR-driven 5.5-fold and 6.5-fold induction responses to omeprazole and 10 μM rifampicin were attenuated to 4-fold and 3.5-fold, respectively. Nano-silver particles alone showed no induction. In 1A2DRE cells, the AhR-driven 5.5-fold induction response to omeprazole was attenuated to 4-fold. In 1A2DRE cells, nano-silver alone elicited slight induction at 1 μg/ml. The inhibition of human CYP-selective activities by nano-silver particles in vitro was proportional to the silver:microsomal protein ratio. At a fixed (0.5 mg/ml) protein concentration, CYP-selective activities differed in sensitivity (IC50 value). Coumarin 7-hydroxylation and 7-ethoxy-4-trifluoromethylcoumarin O-deethylation exhibited the highest IC50 values (33.5 and 31.9 μM respectively) and S-mephenytoin 4-hydroxylation the lowest (6.4 μM). Other IC50 values were, in ascending order, 8.0 - 9.3 μM (testosterone 6β-hydroxylation, 7-benzyloxyquinoline debenzylation and diclofenac 4-hydroxylation), 16.0 μM (chlorzoxazone 6-hydroxylation), 21.2 μM (7-methoxy-4-(aminomethyl)-coumarin O-demethylation), and 24.4 μM (7-methoxyresorufin O-demethylation). Investigated at 70 μM nano-silver, microsomal NADPH cytochrome c reductase activities were inhibited <12%. Extrapolating from in vitro observations, nano-silver particles reaching the liver can be anticipated to be a potential source of drug-drug interactions.