Disruption of dioxin-inducible phase I and phase II gene expression patterns by cadmium, chromium, and arsenic

Citation
A. Maier et al., Disruption of dioxin-inducible phase I and phase II gene expression patterns by cadmium, chromium, and arsenic, MOL CARCINO, 28(4), 2000, pp. 225-235
Citations number
71
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
MOLECULAR CARCINOGENESIS
ISSN journal
08991987 → ACNP
Volume
28
Issue
4
Year of publication
2000
Pages
225 - 235
Database
ISI
SICI code
0899-1987(200008)28:4<225:DODPIA>2.0.ZU;2-H
Abstract
Recent work suggesting that cellular oxidative stress exerts an inhibitory effect on aromatic hydrocarbon receptor (AHR)-dependent gene expression led us to test the hypothesis that pro-oxidant environmental pollutants might alter the induction of detoxification genes by 2,3,7,8-tetrachlorodibenzo-p -dioxin (TCDD), an AHR ligand. We found that, in mouse hepatoma Hepa-l cell s, TCDD-inducible cytochrome P450, Cyp1a1, and nicotinamide adenine dinucle otide phosphate-quinone oxidoreductase (Nqo1) mRNA accumulation were differ entially affected by cadmium (Cd2+), chromium (Cr6+), and arsenic (As3+). C admium or arsenic did not change Cyp1a1 mRNA levels but did enhance TCDD-in ducible levels of Nqo1 mRNA, an effect that paralleled the ability of these metals to activate a beta-galactosidase gene reporter system regulated by an electrophile response promoter element. Chromium inhibited mRNA accumula tion for both Cyp1a1 and Nqo1. Manipulation of cellular thiol status did no t modify the response to combined chromium-TCDD exposure, suggesting that t he response was not caused by oxidative stress. Chromium did not block DNA- binding competence of the AHR and did not have an effect on mRNA stability, but it inhibited Cyp1a1 gene transcription and the expression of an AHR-de pendent luciferase reporter. These data indicate that coexposure to prooxid ant metals and AHR ligands, which is common in the environment, can disrupt the regulation of phase I and phase II detoxification genes, leading to im balances in gene expression that may have important consequences for the to xicity of complex mixtures. (C) 2000 Wiley-Liss, inc.