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

Journal Article · Fri Apr 01 04:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.01.008· OSTI ID:21535264

Rong, Zhang ^[1]; Liping, Ma; Xiaolan, Wu ^[1]; Guoyu, Pan ^[2]; Haiping, Hao; Fang, Zhou; Jiye, A; Changhui, Liu; Hua, Ai; Lili, Shang; Haiyan, Gao; Ying, Peng; Ping, Wan; Hui, Wu ^[1]

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1. Key Laboratory of Drug Metabolism and Pharmacokinetics, Key Unit of SATCM for Pharmacokinetics Methodology of TCM Complex Prescription, China Pharmaceutical University, Nanjing (China)
2. Metabolism and Pharmacokinetics (MAP), Novartis Institute of Biomedical Research (NIBR), 250 Massachusetts Avenue, Cambridge, Massachusetts (United States)

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.

• OSTI ID: 21535264
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 252; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACTINOMYCIN
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ANTIMITOTIC DRUGS
ANTINEOPLASTIC DRUGS
AROMATICS
CARCINOMAS
CONDENSED AROMATICS
CYTOCHROMES
DISEASES
DRUGS
GENES
HEPATOMAS
HYDROCARBONS
MEMBRANE PROTEINS
MESSENGER-RNA
NEOPLASMS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
PIGMENTS
PROTEINS
PYRENE
RECEPTORS
RNA
TRANSCRIPTION