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

被引:80
作者
Keum, Young-Sam
Han, Yong-Hae
Liew, Celine
Kim, Jung-Hwan
Xu, Changjiang
Yuan, Xiaoling
Shakarjian, Michael P.
Chong, Saeho
Kong, Ah-Ng
机构
[1] Rutgers State Univ, Dept Pharmaceut, Ernest Mario Sch Pharm, Piscataway, NJ 08854 USA
[2] Bristol Myers Squibb Pharmaceut, Dept Metab & Pharmacokinet, Princeton, NJ USA
[3] Natl Univ Singapore, Dept Pharm, S-117543 Singapore, Singapore
[4] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, Piscataway, NJ 08854 USA
关键词
butylated hydroxyanisole (BHA); mitogen-activated protein kinases (MAPKs); Nrf2; tert-butylhydroquinone (tBHQ);
D O I
10.1007/s11095-006-9094-2
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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.
引用
收藏
页码:2586 / 2594
页数:9
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