当前位置： SCI文献检索 > MOLECULAR PHARMACOLOGY期刊下所有文献 > Arsenite inhibition of CYP1A1 induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin is independent of cell cycle arrest.

Arsenite inhibition of CYP1A1 induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin is independent of cell cycle arrest.

Abstract：

:We show here that arsenite (As(3+)) elicits multiple effects on gene control, such as the interruption of cell cycle control by initiating G(2)/M arrest as well as inhibiting the aryl hydrocarbon (Ah) receptor-mediated 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible expression of CYP1A1. This raises the question as to whether As(3+) is selectively inhibiting TCDD induction of CYP1A1 independent of cell cycle control. As(3+) stimulated a concentration-dependent increase in G(2)/M phase arrest that was detected at 12.5 microM As(3). However, cotreatment of HepG2 cells with TCDD and concentrations of As(3+) as low as 0.5 microM stimulated a pronounced decrease in the induction of CYP1A1-dependent ethoxyresorufin-O-deethylase activity and protein, indicating that the inhibition of CYP1A1 induction by As(3+) was considerably more sensitive than As(3+)-initiated cell cycle arrest. Low concentrations of As(3+) also initiate a dose-dependent reduction in TCDD-induced mouse Cyp1a1 as well as human CYP1A1 in primary hepatocytes cultured from transgenic CYP1A1N(+/-) mice. Because primary hepatocytes in culture are quiescent, these results indicate that the actions of As(3+) on TCDD-initiated induction of CYP1A1 are independent of cell cycle control. As(3+) does not impact on Ah receptor function as evaluated by nuclear transport and binding to xenobiotic responsive element sequences, but it does reduce TCDD-induced CYP1A1 mRNA, a property that is concordant with RNA polymerase II association to the gene and the reduction in transcriptional heteronuclear RNA. We conclude from these studies that interruption of CYP1A1-induced transcription by As(3+) is not dependent upon cell cycle arrest.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Bonzo JA,Chen S,Galijatovic A,Tukey RH

doi

10.1124/mol.104.006130

keywords:

subject

Has Abstract

pub_date

2005-04-01 00:00:00

pages

1247-56

issue

4

eissn

0026-895X

issn

1521-0111

pii

mol.104.006130

journal_volume

67

pub_type

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