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

  • Young-Sam Keum
  • Yong-Hae Han
  • Celine Liew
  • Jung-Hwan Kim
  • Changjiang Xu
  • Xiaoling Yuan
  • Michael P. Shakarjian
  • Saeho Chong
  • Ah-Ng Kong
Research Paper

DOI: 10.1007/s11095-006-9094-2

Cite this article as:
Keum, YS., Han, YH., 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)Nrf2tert-butylhydroquinone (tBHQ)

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Young-Sam Keum
    • 1
  • Yong-Hae Han
    • 2
  • Celine Liew
    • 3
  • Jung-Hwan Kim
    • 1
  • Changjiang Xu
    • 1
  • Xiaoling Yuan
    • 1
  • Michael P. Shakarjian
    • 4
  • Saeho Chong
    • 2
  • Ah-Ng Kong
    • 1
  1. 1.Department of Pharmaceutics, Ernest Mario School of PharmacyRutgers, The State University of New JerseyPiscatawayUSA
  2. 2.Department of Metabolism and PharmacokineticsBristol Myers Squibb PharmaceuticalsPrincetonUSA
  3. 3.Department of PharmacyNational University of SingaporeSingaporeSingapore
  4. 4.Department of MedicineUMDNJ-Robert Wood Johnson Medical SchoolPiscatawayUSA