title: Nanosilver particle effects on drug metabolism in vitro.
abstract: 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 LD(50) 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 (IC(50) value). Coumarin 7-hydroxylation and 7-ethoxy-4-trifluoromethylcoumarin O-deethylation exhibited the highest IC(50) values (33.5 and 31.9 μM, respectively) and S-mephenytoin 4-hydroxylation exhibited the lowest (6.4 μM). Other IC(50) 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Lamb
authors.forename: Laura B
authors.initials: LB
authors.lastname: Hathaway
authors.forename: Mark A
authors.initials: MA
authors.lastname: Munger
authors.forename: Judy L
authors.initials: JL
authors.lastname: Raucy
authors.forename: Michael R
authors.initials: MR
authors.lastname: Franklin
mesh_terms: D018938:Caco-2 Cells; D056945:Hep G2 Cells; D006801:Humans; D053758:Nanoparticles; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000187:drug effects; D012834:Silver / Q000494:pharmacology*
chemical_list: D004364:Pharmaceutical Preparations; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D012834:Silver