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Original Article

Arsenite Inhibition of CYP1A1 Induction by 2,3,7,8-Tetrachlorodibenzo-p-dioxin Is Independent of Cell Cycle Arrest

Laboratory of Environmental Toxicology, Departments of Pharmacology, Chemistry & Biochemistry, University of California, San Diego, La Jolla, California

Abstract

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.

Address correspondence to: Dr. Robert H. Tukey, Leichtag Biomedical Research Bldg., Room 211, University of California, San Diego, La Jolla, CA 92093-0722. E-mail: rtukey{at}ucsd.edu