The Impact of Porous Silicon Nanoparticles on Human Cytochrome P450 Metabolism in Human Liver Microsomes In Vitro

Elisa Ollikainen, Dongfei Liu, Arttu Kallio, Ermei Mäkilä, Hongbo Zhang, Jarno Salonen, Helder Almeida Santos, Tiina M. Sikanen

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Engineered nanoparticles are increasingly used as drug carriers in pharmaceutical formulations. This study focuses on the hitherto unaddressed impact of porous silicon (PSi) nanoparticles on human cytochrome P450 (CYP) metabolism, which is the major detoxification route of most pharmaceuticals and other xenobiotics. Three different surface chemistries, including thermally carbonized PSi (TCPSi), aminopropylsilane-modified TCPSi (APTES-TCPSi) and alkyne-terminated thermally hydrocarbonized PSi (Alkyne-THCPSi), were compared for their effects on the enzyme kinetics of the major CYP isoforms (CYP1A2, CYP2A6, CYP2D6, and CYP3A4) in human liver microsomes (HLM) in vitro. The enzyme kinetic parameters, Km and Vmax, and the intrinsic clearance (CLint) were determined using FDA-recommended, isoenzyme-specific model reactions with and without PSi nanoparticles. Data revealed statistically significant alterations of most isoenzyme activities in HLM in the presence of nanoparticles at 1 mg/mL concentration, and polymorphic CYP2D6 was the most vulnerable to enzyme inhibition. However, the observed CYP2D6 inhibition was shown to be dose-dependent in case of TCPSi and Alkyne-THCPSi nanoparticles and attenuated at the concentrations below 2 g/mL.. Adsorption of the probe substrates onto the hydrophobic Alkyne-THCPSi particles was also observed and taken into account in the determination of the kinetic parameters. Three polymer additives commonly used in pharmaceutical nanoformulations (Pluronics F68 and F127, and polyvinylalcohol) were also separately screened for their effects on CYP isoenzyme activities. These polymers had less effect on the enzyme kinetic parameters, and resulted in increased activity rather than enzyme inhibition, in contrast to the PSi nanoparticles. Although the chosen subcellular model (HLM) is not able to predict the cellular disposition of PSi nanoparticles in hepatocytes and thus provides limited information of probability of CYP interactions in vivo, the present study suggests that mechanistic interactions by the PSi nanoparticles or the polymer stabilizers may appear if these are effectively uptaken by the hepatocytes.
Original languageEnglish
JournalEuropean Journal of Pharmaceutical Sciences
Volume104
Pages (from-to)124–132
Number of pages9
ISSN0928-0987
DOIs
Publication statusPublished - 15 Jun 2017
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 317 Pharmacy
  • Porous silicon
  • Nanoparticles
  • Drug metabolism
  • Cytochrome P450
  • Pluronics
  • PLASMA-PROTEIN ADSORPTION
  • DRUG-DELIVERY
  • MESOPOROUS SILICON
  • SURFACE-CHEMISTRY
  • GOLD NANOPARTICLES
  • CELLULAR UPTAKE
  • MICROPARTICLES
  • BIOCOMPATIBILITY
  • SIZE
  • BIODISTRIBUTION

Cite this

@article{e627b092844d447bb12aaa1bd9cfb18f,
title = "The Impact of Porous Silicon Nanoparticles on Human Cytochrome P450 Metabolism in Human Liver Microsomes In Vitro",
abstract = "Engineered nanoparticles are increasingly used as drug carriers in pharmaceutical formulations. This study focuses on the hitherto unaddressed impact of porous silicon (PSi) nanoparticles on human cytochrome P450 (CYP) metabolism, which is the major detoxification route of most pharmaceuticals and other xenobiotics. Three different surface chemistries, including thermally carbonized PSi (TCPSi), aminopropylsilane-modified TCPSi (APTES-TCPSi) and alkyne-terminated thermally hydrocarbonized PSi (Alkyne-THCPSi), were compared for their effects on the enzyme kinetics of the major CYP isoforms (CYP1A2, CYP2A6, CYP2D6, and CYP3A4) in human liver microsomes (HLM) in vitro. The enzyme kinetic parameters, Km and Vmax, and the intrinsic clearance (CLint) were determined using FDA-recommended, isoenzyme-specific model reactions with and without PSi nanoparticles. Data revealed statistically significant alterations of most isoenzyme activities in HLM in the presence of nanoparticles at 1 mg/mL concentration, and polymorphic CYP2D6 was the most vulnerable to enzyme inhibition. However, the observed CYP2D6 inhibition was shown to be dose-dependent in case of TCPSi and Alkyne-THCPSi nanoparticles and attenuated at the concentrations below 2 g/mL.. Adsorption of the probe substrates onto the hydrophobic Alkyne-THCPSi particles was also observed and taken into account in the determination of the kinetic parameters. Three polymer additives commonly used in pharmaceutical nanoformulations (Pluronics F68 and F127, and polyvinylalcohol) were also separately screened for their effects on CYP isoenzyme activities. These polymers had less effect on the enzyme kinetic parameters, and resulted in increased activity rather than enzyme inhibition, in contrast to the PSi nanoparticles. Although the chosen subcellular model (HLM) is not able to predict the cellular disposition of PSi nanoparticles in hepatocytes and thus provides limited information of probability of CYP interactions in vivo, the present study suggests that mechanistic interactions by the PSi nanoparticles or the polymer stabilizers may appear if these are effectively uptaken by the hepatocytes.",
keywords = "317 Pharmacy, Porous silicon , Nanoparticles , Drug metabolism , Cytochrome P450 , Pluronics , PLASMA-PROTEIN ADSORPTION , DRUG-DELIVERY , MESOPOROUS SILICON , SURFACE-CHEMISTRY , GOLD NANOPARTICLES , CELLULAR UPTAKE , MICROPARTICLES , BIOCOMPATIBILITY , SIZE , BIODISTRIBUTION",
author = "Elisa Ollikainen and Dongfei Liu and Arttu Kallio and Ermei M{\"a}kil{\"a} and Hongbo Zhang and Jarno Salonen and {Almeida Santos}, Helder and Sikanen, {Tiina M.}",
year = "2017",
month = "6",
day = "15",
doi = "10.1016/j.ejps.2017.03.039",
language = "English",
volume = "104",
pages = "124–132",
journal = "European Journal of Pharmaceutical Sciences",
issn = "0928-0987",
publisher = "Elsevier Scientific Publ. Co",

}

The Impact of Porous Silicon Nanoparticles on Human Cytochrome P450 Metabolism in Human Liver Microsomes In Vitro. / Ollikainen, Elisa ; Liu, Dongfei; Kallio, Arttu; Mäkilä, Ermei ; Zhang, Hongbo; Salonen, Jarno; Almeida Santos, Helder; Sikanen, Tiina M.

In: European Journal of Pharmaceutical Sciences, Vol. 104, 15.06.2017, p. 124–132.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - The Impact of Porous Silicon Nanoparticles on Human Cytochrome P450 Metabolism in Human Liver Microsomes In Vitro

AU - Ollikainen, Elisa

AU - Liu, Dongfei

AU - Kallio, Arttu

AU - Mäkilä, Ermei

AU - Zhang, Hongbo

AU - Salonen, Jarno

AU - Almeida Santos, Helder

AU - Sikanen, Tiina M.

PY - 2017/6/15

Y1 - 2017/6/15

N2 - Engineered nanoparticles are increasingly used as drug carriers in pharmaceutical formulations. This study focuses on the hitherto unaddressed impact of porous silicon (PSi) nanoparticles on human cytochrome P450 (CYP) metabolism, which is the major detoxification route of most pharmaceuticals and other xenobiotics. Three different surface chemistries, including thermally carbonized PSi (TCPSi), aminopropylsilane-modified TCPSi (APTES-TCPSi) and alkyne-terminated thermally hydrocarbonized PSi (Alkyne-THCPSi), were compared for their effects on the enzyme kinetics of the major CYP isoforms (CYP1A2, CYP2A6, CYP2D6, and CYP3A4) in human liver microsomes (HLM) in vitro. The enzyme kinetic parameters, Km and Vmax, and the intrinsic clearance (CLint) were determined using FDA-recommended, isoenzyme-specific model reactions with and without PSi nanoparticles. Data revealed statistically significant alterations of most isoenzyme activities in HLM in the presence of nanoparticles at 1 mg/mL concentration, and polymorphic CYP2D6 was the most vulnerable to enzyme inhibition. However, the observed CYP2D6 inhibition was shown to be dose-dependent in case of TCPSi and Alkyne-THCPSi nanoparticles and attenuated at the concentrations below 2 g/mL.. Adsorption of the probe substrates onto the hydrophobic Alkyne-THCPSi particles was also observed and taken into account in the determination of the kinetic parameters. Three polymer additives commonly used in pharmaceutical nanoformulations (Pluronics F68 and F127, and polyvinylalcohol) were also separately screened for their effects on CYP isoenzyme activities. These polymers had less effect on the enzyme kinetic parameters, and resulted in increased activity rather than enzyme inhibition, in contrast to the PSi nanoparticles. Although the chosen subcellular model (HLM) is not able to predict the cellular disposition of PSi nanoparticles in hepatocytes and thus provides limited information of probability of CYP interactions in vivo, the present study suggests that mechanistic interactions by the PSi nanoparticles or the polymer stabilizers may appear if these are effectively uptaken by the hepatocytes.

AB - Engineered nanoparticles are increasingly used as drug carriers in pharmaceutical formulations. This study focuses on the hitherto unaddressed impact of porous silicon (PSi) nanoparticles on human cytochrome P450 (CYP) metabolism, which is the major detoxification route of most pharmaceuticals and other xenobiotics. Three different surface chemistries, including thermally carbonized PSi (TCPSi), aminopropylsilane-modified TCPSi (APTES-TCPSi) and alkyne-terminated thermally hydrocarbonized PSi (Alkyne-THCPSi), were compared for their effects on the enzyme kinetics of the major CYP isoforms (CYP1A2, CYP2A6, CYP2D6, and CYP3A4) in human liver microsomes (HLM) in vitro. The enzyme kinetic parameters, Km and Vmax, and the intrinsic clearance (CLint) were determined using FDA-recommended, isoenzyme-specific model reactions with and without PSi nanoparticles. Data revealed statistically significant alterations of most isoenzyme activities in HLM in the presence of nanoparticles at 1 mg/mL concentration, and polymorphic CYP2D6 was the most vulnerable to enzyme inhibition. However, the observed CYP2D6 inhibition was shown to be dose-dependent in case of TCPSi and Alkyne-THCPSi nanoparticles and attenuated at the concentrations below 2 g/mL.. Adsorption of the probe substrates onto the hydrophobic Alkyne-THCPSi particles was also observed and taken into account in the determination of the kinetic parameters. Three polymer additives commonly used in pharmaceutical nanoformulations (Pluronics F68 and F127, and polyvinylalcohol) were also separately screened for their effects on CYP isoenzyme activities. These polymers had less effect on the enzyme kinetic parameters, and resulted in increased activity rather than enzyme inhibition, in contrast to the PSi nanoparticles. Although the chosen subcellular model (HLM) is not able to predict the cellular disposition of PSi nanoparticles in hepatocytes and thus provides limited information of probability of CYP interactions in vivo, the present study suggests that mechanistic interactions by the PSi nanoparticles or the polymer stabilizers may appear if these are effectively uptaken by the hepatocytes.

KW - 317 Pharmacy

KW - Porous silicon

KW - Nanoparticles

KW - Drug metabolism

KW - Cytochrome P450

KW - Pluronics

KW - PLASMA-PROTEIN ADSORPTION

KW - DRUG-DELIVERY

KW - MESOPOROUS SILICON

KW - SURFACE-CHEMISTRY

KW - GOLD NANOPARTICLES

KW - CELLULAR UPTAKE

KW - MICROPARTICLES

KW - BIOCOMPATIBILITY

KW - SIZE

KW - BIODISTRIBUTION

UR - https://www.journals.elsevier.com/european-journal-of-pharmaceutical-sciences/

U2 - 10.1016/j.ejps.2017.03.039

DO - 10.1016/j.ejps.2017.03.039

M3 - Article

VL - 104

SP - 124

EP - 132

JO - European Journal of Pharmaceutical Sciences

JF - European Journal of Pharmaceutical Sciences

SN - 0928-0987

ER -