Arsenite inhibition of CYP1A1 induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin is independent of cell cycle arrest.
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.
Bonzo
Jessica A
JA
Leichtag Biomedical Research Bldg., Room 211, University of California-San Diego, La Jolla, CA 92093-0722, USA.
Chen
Shujuan
S
Galijatovic
Alema
A
Tukey
Robert H
RH
D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D018053:Arsenites; D000072317:Polychlorinated Dibenzodioxins; D019363:Cytochrome P-450 CYP1A1; C015001:arsenite