In vivo pharmacokinetics, activation of MAPK signaling and induction of phase II/III drug metabolizing enzymes/transporters by cancer chemopreventive compound BHA in the mice

Rong Hu, Guoxiang Shen, Usha Rao Yerramilli, Wen Lin, Changjiang Xu, Sujit Nair, Ah Ng Tony Kong

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Phenolic antioxidant butylated hydroxyanisole (BHA) is a commonly used food preservative with broad biological activities, including protection against chemical-induced carcinogenesis, acute toxicity of chemicals, modulation of macromolecule synthesis and immune response, induction of phase II detoxifying enzymes, as well as its undesirable potential tumor-promoting activities. Understanding the molecular basis underlying these diverse biological actions of BHA is thus of great importance. Here we studied the pharmacokinetics, activation of signaling kinases and induction of phase II/III drug metabolizing enzymes/transporter gene expression by BHA in the mice. The peak plasma concentration of BHA achieved in our current study after oral administration of 200 mg/kg BHA was around 10 μM. This in vivo concentration might offer some insights for the many in vitro cell culture studies on signal transduction and induction of phase II genes using similar concentrations. The oral bioavailability (F) of BHA was about 43% in the mice. In the mouse liver, BHA induced the expression of phase II genes including NQO-1, HO-1, γ-GCS, GST-pi and UGT 1A6, as well as some of the phase III transporter genes, such as MRP1 and Slco1b2. In addition, BHA activated distinct mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), as well as p38, suggesting that the MAPK pathways may play an important role in early signaling events leading to the regulation of gene expression including phase II drug metabolizing and some phase III drug transporter genes. This is the first study to demonstrate the in vivo pharmacokinetics of BHA, the in vivo activation of MAPK signaling proteins, as well as the in vivo induction of Phase II/III drug metabolizing enzymes/transporters in the mouse livers.

Original languageEnglish (US)
Pages (from-to)911-920
Number of pages10
JournalArchives of Pharmacal Research
Volume29
Issue number10
DOIs
StatePublished - Oct 31 2006

Fingerprint

Butylated Hydroxyanisole
Pharmacokinetics
Mitogen-Activated Protein Kinases
Chemical activation
Enzymes
Pharmaceutical Preparations
Neoplasms
Genes
Gene expression
Liver
Food Preservatives
Signal transduction
JNK Mitogen-Activated Protein Kinases
Extracellular Signal-Regulated MAP Kinases
Gene Expression Regulation
p38 Mitogen-Activated Protein Kinases
Bioactivity
Macromolecules
Cell culture
Protein Kinases

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery
  • Organic Chemistry

Keywords

  • Butylated hydroxyanisole
  • MAPKs
  • Pharmacokinetics
  • Phase II gene
  • Transporter

Cite this

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title = "In vivo pharmacokinetics, activation of MAPK signaling and induction of phase II/III drug metabolizing enzymes/transporters by cancer chemopreventive compound BHA in the mice",
abstract = "Phenolic antioxidant butylated hydroxyanisole (BHA) is a commonly used food preservative with broad biological activities, including protection against chemical-induced carcinogenesis, acute toxicity of chemicals, modulation of macromolecule synthesis and immune response, induction of phase II detoxifying enzymes, as well as its undesirable potential tumor-promoting activities. Understanding the molecular basis underlying these diverse biological actions of BHA is thus of great importance. Here we studied the pharmacokinetics, activation of signaling kinases and induction of phase II/III drug metabolizing enzymes/transporter gene expression by BHA in the mice. The peak plasma concentration of BHA achieved in our current study after oral administration of 200 mg/kg BHA was around 10 μM. This in vivo concentration might offer some insights for the many in vitro cell culture studies on signal transduction and induction of phase II genes using similar concentrations. The oral bioavailability (F) of BHA was about 43{\%} in the mice. In the mouse liver, BHA induced the expression of phase II genes including NQO-1, HO-1, γ-GCS, GST-pi and UGT 1A6, as well as some of the phase III transporter genes, such as MRP1 and Slco1b2. In addition, BHA activated distinct mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), as well as p38, suggesting that the MAPK pathways may play an important role in early signaling events leading to the regulation of gene expression including phase II drug metabolizing and some phase III drug transporter genes. This is the first study to demonstrate the in vivo pharmacokinetics of BHA, the in vivo activation of MAPK signaling proteins, as well as the in vivo induction of Phase II/III drug metabolizing enzymes/transporters in the mouse livers.",
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In vivo pharmacokinetics, activation of MAPK signaling and induction of phase II/III drug metabolizing enzymes/transporters by cancer chemopreventive compound BHA in the mice. / Hu, Rong; Shen, Guoxiang; Yerramilli, Usha Rao; Lin, Wen; Xu, Changjiang; Nair, Sujit; Kong, Ah Ng Tony.

In: Archives of Pharmacal Research, Vol. 29, No. 10, 31.10.2006, p. 911-920.

Research output: Contribution to journalArticle

TY - JOUR

T1 - In vivo pharmacokinetics, activation of MAPK signaling and induction of phase II/III drug metabolizing enzymes/transporters by cancer chemopreventive compound BHA in the mice

AU - Hu, Rong

AU - Shen, Guoxiang

AU - Yerramilli, Usha Rao

AU - Lin, Wen

AU - Xu, Changjiang

AU - Nair, Sujit

AU - Kong, Ah Ng Tony

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KW - Phase II gene

KW - Transporter

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