Induction of cytochromes P450 1A1 and 1A2 by tanshinones in human HepG2 hepatoma cell line

被引：40

作者：

Zhang, Rong ^{[1
]}

Sun, Jianguo ^{[1
]}

Ma, Liping ^{[1
]}

Wu, Xiaolan ^{[1
]}

Pan, Guoyu ^{[2
]}

Hao, Haiping ^{[1
]}

Zhou, Fang ^{[1
]}

Jiye, A. ^{[1
]}

Liu, Changhui ^{[1
]}

Ai, Hua ^{[1
]}

Shang, Lili ^{[1
]}

Gao, Haiyan ^{[1
]}

Peng, Ying ^{[1
]}

Wan, Ping ^{[1
]}

Wu, Hui ^{[1
]}

Wang, Guangji ^{[1
]}

机构：

[1] China Pharmaceut Univ, Key Unit SATCM Pharmacokinet Methodol TCM Complex, Key Lab Drug Metab & Pharmacokinet, Nanjing 210009, Peoples R China

[2] Novartis Inst Biomed Res NIBR, Metab & Pharmacokinet MAP, Cambridge, MA USA

来源：

TOXICOLOGY AND APPLIED PHARMACOLOGY | 2011年 / 252卷 / 01期

基金：

中国国家自然科学基金;

关键词：

CYP1A1; CYP1A2; Tanshinone; AhR; Induction; ARYL-HYDROCARBON RECEPTOR; PRIMARY HUMAN HEPATOCYTES; GENE-EXPRESSION; TRANSCRIPTIONAL INDUCTION; SALVIA-MILTIORRHIZA; SPECIES-DIFFERENCES; ANTICANCER ACTIVITY; CYP1A1; EXPRESSION; DANSHEN EXTRACT; DNA-DAMAGE;

D O I：

10.1016/j.taap.2011.01.008

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

Diterpenoid tanshinones including tanshinone IIA (TIIA), cryptotanshinone (CTS), tanshinone I (TI) and dihydrotanshinone I (DHTI) are the major bioactive components from Danshen. The major aim of our present study was to investigate the induction potential of these four main components of tanshinones (TIIA, CTS, TI, and DHTI) on the expression of CYP1A1 and CYP1A2 in HepG2 cells. Our results showed that all of these four tanshinones caused a significant time- and concentration-dependent increase in the amount of CYP1A1/2 expression in HepG2 cells. These induction effects were further characterized through transcriptional regulation: the induction of CYP1A1/2 mRNA level by tanshinones was completely blocked by the transcription inhibitor actinomycin D; the expression of CYP1A1/2 heterogeneous nuclear RNA was induced by tanshinone treatment; and CYP1A1 mRNA stability was not influenced by these tanshinones. Interestingly, tanshinones plus B[a]P produced additive/synergistic effect on CYP1A1/2 induction. In addition, the tanshinone-induced CYP1A1/2 expression was abolished by the aryl hydrocarbon receptor (AhR) antagonist resveratrol, suggesting an AhR dependent transcription mechanism. In the reporter gene assay, while TI and DHTI significantly induced AhR-dependent luciferase activity, TIIA and CTS failed to induce this activity. Collectively, the tanshinones could induce CYP1A1 and CYP1A2 expression through transcriptional activation mechanism and exert differential effects on activating AhR in HepG2 cells. Our findings suggest that rational administration of tanshinones should be considered with respect to their effect on AhR and CYP1A1/2 expression. (C) 2011 Elsevier Inc. All rights reserved.

引用

页码：18 / 27

页数：10

共 66 条

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Resveratrol Inhibits Dioxin-Induced Expression of Human CYP1A1 and CYP1B1 by Inhibiting Recruitment of the Aryl Hydrocarbon Receptor Complex and RNA Polymerase II to the Regulatory Regions of the Corresponding Genes [J].