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

We show here that arsenite (As3+) 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 As3+ is selectively inhibiting TCDD induction of CYP1A1 independent of cell cycle control. As3+ stimulated a concentration- dependent increase in G(2)/M phase arrest that was detected at 12.5 mu M As3+. However, cotreatment of HepG2 cells with TCDD and concentrations of As3+ as low as 0.5 mu M 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.