PT - JOURNAL ARTICLE AU - Bonzo, Jessica A. AU - Chen, Shujuan AU - Galijatovic, Alema AU - Tukey, Robert H. TI - Arsenite Inhibition of CYP1A1 Induction by 2,3,7,8-Tetrachlorodibenzo-<em>p</em>-dioxin Is Independent of Cell Cycle Arrest AID - 10.1124/mol.104.006130 DP - 2005 Apr 01 TA - Molecular Pharmacology PG - 1247--1256 VI - 67 IP - 4 4099 - http://molpharm.aspetjournals.org/content/67/4/1247.short 4100 - http://molpharm.aspetjournals.org/content/67/4/1247.full SO - Mol Pharmacol2005 Apr 01; 67 AB - We show here that arsenite (As3+) elicits multiple effects on gene control, such as the interruption of cell cycle control by initiating G2/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 As3+ is selectively inhibiting TCDD induction of CYP1A1 independent of cell cycle control. As3+ stimulated a concentration-dependent increase in G2/M phase arrest that was detected at 12.5 μM As3. However, cotreatment of HepG2 cells with TCDD and concentrations of As3+ as low as 0.5 μM stimulated a pronounced decrease in the induction of CYP1A1-dependent ethoxyresorufin-O-deethylase activity and protein, indicating that the inhibition of CYP1A1 induction by As3+ was considerably more sensitive than As3+-initiated cell cycle arrest. Low concentrations of As3+ 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 As3+ on TCDD-initiated induction of CYP1A1 are independent of cell cycle control. As3+ 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 As3+ is not dependent upon cell cycle arrest.