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
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.