Pharmaceutical Research

, Volume 23, Issue 11, pp 2586–2594

Induction of Heme Oxygenase-1 (HO-1) and NAD[P]H: Quinone Oxidoreductase 1 (NQO1) by a Phenolic Antioxidant, Butylated Hydroxyanisole (BHA) and Its Metabolite, tert-Butylhydroquinone (tBHQ) in Primary-Cultured Human and Rat Hepatocytes

Authors

  • Young-Sam Keum
    • Department of Pharmaceutics, Ernest Mario School of PharmacyRutgers, The State University of New Jersey
  • Yong-Hae Han
    • Department of Metabolism and PharmacokineticsBristol Myers Squibb Pharmaceuticals
  • Celine Liew
    • Department of PharmacyNational University of Singapore
  • Jung-Hwan Kim
    • Department of Pharmaceutics, Ernest Mario School of PharmacyRutgers, The State University of New Jersey
  • Changjiang Xu
    • Department of Pharmaceutics, Ernest Mario School of PharmacyRutgers, The State University of New Jersey
  • Xiaoling Yuan
    • Department of Pharmaceutics, Ernest Mario School of PharmacyRutgers, The State University of New Jersey
  • Michael P. Shakarjian
    • Department of MedicineUMDNJ-Robert Wood Johnson Medical School
  • Saeho Chong
    • Department of Metabolism and PharmacokineticsBristol Myers Squibb Pharmaceuticals
    • Department of Pharmaceutics, Ernest Mario School of PharmacyRutgers, The State University of New Jersey
Research Paper

DOI: 10.1007/s11095-006-9094-2

Cite this article as:
Keum, Y., Han, Y., Liew, C. et al. Pharm Res (2006) 23: 2586. doi:10.1007/s11095-006-9094-2

Abstract

Purpose

This study was aimed to investigate the effects of a phenolic antioxidant, butylated hydroxyanisole (BHA) and its metabolite, tert-butylhydroquinone (tBHQ) on the induction of HO-1, NQO1 and Nrf2 proteins and their regulatory mechanisms in primary-cultured hepatocytes.

Methods

After exposure of BHA and tBHQ to primary-cultured rat and human hepatocytes and mouse neonatal fibroblasts (MFs), Western blot, semi-quantitative RT-PCR and microarray analysis were conducted.

Results

Induction of HO-1, NQO1 and Nrf2 proteins and activation of ERK1/2 and JNK1/2 were observed after BHA and tBHQ treatments in primary-cultured rat and human hepatocytes. Semi-quantitative RT-PCR study and microarray analysis revealed that HO-1 and NQO1 were transcriptionally activated in primary-cultured rat hepatocytes and a substantial transcriptional activation, including HO-1 occurred in primary-cultured human hepatocytes after BHA treatment. Whereas BHA failed to induce HO-1 in wild-type and Nrf2 knock-out MFs, tBHQ strongly induced HO-1 in wild-type, but not in Nrf2 knock-out MFs.

Conclusions

Our data demonstrate that both BHA and tBHQ are strong chemical inducers of HO-1, NQO1 and Nrf2 proteins in primary-cultured human and rat hepatocytes with the activation of MAPK ERK1/2 and JNK1/2. However, in MFs, BHA failed to induce HO-1, whereas tBHQ strongly induced HO-1 in Nrf2 wild-type but not in Nrf2 knock-out, suggesting that Nrf2 is indispensable for tBHQ-induced HO-1 in MF.

Key words

butylated hydroxyanisole (BHA) mitogen-activated protein kinases (MAPKs) Nrf2 tert-butylhydroquinone (tBHQ)

Copyright information

© Springer Science + Business Media, Inc. 2006