Impact of Gold Nanoparticles on Testosterone Metabolism in Human Liver Microsomes.

Gold nanoparticle (AuNP)-protein corona complexes can alter cytochrome P450 (CYP)-mediated testosterone (TST) metabolism by altering their physicochemical properties. We investigated the impact of NP size, surface chemistry, and protein corona in TST metabolism in pooled human liver microsomes (pHLM) employing 40 and 80 nm AuNP functionalized with branched polyethylenimine (BPEI), lipoic acid (LA), and polyethylene glycol (PEG) as well as human plasma protein corona (PC). Individual variation in AuNP-mediated TST metabolism was also characterized among single donor HLM that contained different levels of CYP activities.

Influence of shell compositions of solution blown PVP/PCL core-shell fibers on drug release and cell growth.

Developing a facile means of controlling drug release is of utmost interest in drug delivery systems. In this study, core-shell structured nanofibers containing a water-soluble porogen were fabricated solution blow spinning, to be used as drug-loaded bioactive tissue scaffolds. Hydrophilic polyvinylpyrrolidone (PVP) and hydrophobic poly(ε-caprolactone) (PCL) were chosen to produce the core and the shell compartments of the fiber, respectively.

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.

Modeling gold nanoparticle biodistribution after arterial infusion into perfused tissue: effects of surface coating, size and protein corona.

A detailed understanding of the factors governing nanomaterial biodistribution is needed to rationally design safe nanomedicines. This research details the pharmacokinetics of gold nanoparticle (AuNP) biodistribution after arterial infusion of 40 or 80 nm AuNP (1 μg/ml) into the isolated perfused porcine skin flap (IPPSF). AuNP had surface coatings consisting of neutral polyethylene glycol (PEG), anionic lipoic acid (LA), or cationic branched polyethylenimine (BPEI).

Early stage release control of an anticancer drug by drug-polymer miscibility in a hydrophobic fiber-based drug delivery system.

The drug release profiles of doxorubicin-loaded electrospun fiber mats were investigated with regard to drug-polymer miscibility, fiber wettability and degradability. Doxorubicin in hydrophilic form (Dox-HCl) and hydrophobic free base form (Dox-base) was employed as model drugs, and an aliphatic polyester, poly(lactic acid) (PLA), was used as a drug-carrier matrix. When hydrophilic Dox-HCl was directly mixed with PLA solution, drug molecules formed large aggregates on the fiber surface or in the fiber core, due to poor drug-polymer compatibility.

Doxorubicin Release Controlled by Induced Phase Separation and Use of a Co-Solvent.

Electrospun-based drug delivery is emerging as a versatile means of localized therapy; however, controlling the release rates of active agents still remains as a key question. We propose a facile strategy to control the drug release behavior from electrospun fibers by a simple modification of polymer matrices. Polylactic acid (PLA) was used as a major component of the drug-carrier, and doxorubicin hydrochloride (Dox) was used as a model drug.

Protein corona modulation of hepatocyte uptake and molecular mechanisms of gold nanoparticle toxicity.

Protein corona formation over gold nanoparticles (AuNP) can modulate cellular responses by altering AuNP physicochemical properties. The liver plays an essential role in metabolism, detoxification and elimination of xenobiotics and drugs as well as circulating NP clearance. We investigated human hepatic uptake of 40 and 80 nm AuNP with branched polyethylenimine (BPEI), lipoic acid (LA) and polyethylene glycol (PEG) coatings as well as human plasma protein (HP) and human serum albumin (HSA) coronas.

Oxidative stress response in canine in vitro liver, kidney and intestinal models with seven potential dietary ingredients.

In vitro cell culture systems are a useful tool to rapidly assess the potential safety or toxicity of chemical constituents of food. Here, we investigated oxidative stress and organ-specific antioxidant responses by 7 potential dietary ingredients using canine in vitro culture of hepatocytes, proximal tubule cells (CPTC), bone marrow-derived mesenchymal stem cells (BMSC) and enterocyte-like cells (ELC). Cellular production of free radical species by denatonium benzoate (DB), epigallocatechin gallate (EPI), eucalyptol (EUC), green tea catechin extract (GTE) and sodium copper chlorophyllin (SCC), tetrahydroisohumulone (TRA) as well as xylitol (XYL) were continuously measured for reactive oxygen/nitrogen species (ROS/RNS) and superoxide (SO) for up to 24h.

Development of 3D dynamic flow model of human liver and its application to prediction of metabolic clearance of 7-ethoxycoumarin.

Primary and cryopreserved hepatocytes and immortalized hepatic cell lines in static two-dimensional monolayer culture format have been widely used as in vitro liver models for studies of xenobiotic metabolism, enzyme induction, hepatocyte regeneration, and hepatotoxicity. However, the tissue structure and metabolic capacity in these liver models are often ill-defined and are not well preserved compared to in vivo liver-specific architecture and functions. For this reason, we developed a three-dimensional (3D) dynamic flow model with primary human hepatocytes, which was optimized for cell seeding density, medium composition, and extracellular matrix proteins.

In vitro intestinal and hepatic metabolism of Di(2-ethylhexyl) phthalate (DEHP) in human and rat.

Species and organ differences in the intrinsic clearance and the enzymes involved in the metabolism of DEHP were examined in subcellular fractions of the intestine and liver as well as by recombinant cytochrome P450 (CYP) isoforms of human and rat. Estimated clearance (CLint) of DEHP via esterase-mediated pathway in human intestine was 2.4-fold greater than that in human liver while its value in rat intestine was 1.

Development of multi-route physiologically-based pharmacokinetic models for ethanol in the adult, pregnant, and neonatal rat.

Biofuel blends of 10% ethanol (EtOH) and gasoline are common in the USA, and higher EtOH concentrations are being considered (15-85%). Currently, no physiologically-based pharmacokinetic (PBPK) models are available to describe the kinetics of EtOH-based biofuels. PBPK models were developed to describe life-stage differences in the kinetics of EtOH alone in adult, pregnant, and neonatal rats for inhalation, oral, and intravenous routes of exposure, using data available in the open literature.

In vitro metabolism of di(2-ethylhexyl) phthalate (DEHP) by various tissues and cytochrome P450s of human and rat.

In vitro metabolism of DEHP by subcellular fractions of human brain, intestine, kidney, liver, lung, skin, testis, rat liver and recombinant CYP isoforms of human and rat was investigated using LC-MS/MS. DEHP was rapidly hydrolyzed to mono(2-ethylhexyl) phthalate (MEHP) in 12 microsomal/cytosolic fractions of selected 7 human organs and rat liver but not in microsomal fractions of human brain and human female skin. MEHP was metabolized to CYP-mediated oxidative and dealkylated metabolites in human and rat liver and at a lower rate in human intestine.

Inhibition of fipronil and nonane metabolism in human liver microsomes and human cytochrome P450 isoforms by chlorpyrifos.

Previous studies have established that chlorpyrifos (CPS), fipronil, and nonane can all be metabolized by human liver microsomes (HLM) and a number of cytochrome P450 (CYP) isoforms. However, metabolic interactions between these three substrates have not been described. In this study the effect of either coincubation or preincubation of CPS with HLM or CYP isoforms with either fipronil or nonane as substrate was investigated.

Metabolism of chlorpyrifos and chlorpyrifos oxon by human hepatocytes.

The metabolism of chlorpyrifos (CPS) and chlorpyrifos oxon (CPO) by human hepatocytes and human liver S9 fractions was investigated using LC-MS/MS. Cytochrome P450 (CYP)-dependent and phase II-related products were determined following incubation with CPS and CPO. CYP-related products, 3,5,6-trichloro-2-pyridinol (TCP), diethyl thiophosphate, and dealkylated CPS, were found following CPS treatment and dealkylated CPO following CPO treatment.