TY - JOUR T1 - Nanosilver Particle Effects on Drug Metabolism In Vitro JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2246 LP - 2251 DO - 10.1124/dmd.110.035238 VL - 38 IS - 12 AU - John G. Lamb AU - Laura B. Hathaway AU - Mark A. Munger AU - Judy L. Raucy AU - Michael R. Franklin Y1 - 2010/12/01 UR - http://dmd.aspetjournals.org/content/38/12/2246.abstract N2 - Nanosilver particles are present in consumer and health care products. Their effects on human microsomal cytochrome P450 (P450) activities and induction in luciferase reporter-engineered Caco-2 (MDR1.C) and HepG2 (DPX2 and 1A2DRE) cells have been investigated. The LD50 values were ∼4 μg silver/ml for HepG2 and 5 μg/ml for Caco-2 cells. At silver concentrations that showed no decreased cell viability (<1 μg silver/ml), the pregnane X receptor (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- and 6.5-fold induction responses to omeprazole and 10 μM rifampicin were attenuated to 4- and 3.5-fold, respectively. Nanosilver particles alone showed no induction. In 1A2DRE cells, the aryl hydrocarbon receptor-driven 5.5-fold induction response to omeprazole was attenuated to 4-fold. In 1A2DRE cells, nanosilver alone elicited slight induction at 1 μg/ml. The inhibition of human P450-selective activities by nanosilver particles in vitro was proportional to the silver/microsomal protein ratio. At a fixed (0.5 mg/ml) protein concentration, P450-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 exhibited the lowest (6.4 μM). Other IC50 values were, in ascending order, 8.0 to 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). An investigation of 70 μM nanosilver particles showed that microsomal NADPH cytochrome c reductase activities were inhibited <12%. From our in vitro observations, we extrapolated that nanosilver particles reaching the liver may be a potential source of drug-drug interactions. ER -