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 output: Contribution to journalArticlepeer-review

84 Scopus citations

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.

Original languageEnglish
Pages (from-to)2586-2594
Number of pages9
JournalPharmaceutical Research
Volume23
Issue number11
DOIs
StatePublished - Nov 2006

Keywords

  • Butylated hydroxyanisole (BHA)
  • Mitogen-activated protein kinases (MAPKs)
  • Nrf2
  • tert-butylhydroquinone (tBHQ)

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this