Co-contamination with complex mixtures of carcinogenic metals, such as chromium, and polycyclic aromatic hydrocarbons is a common environmental problem with multiple biological consequences. Chromium exposure alters inducible gene expression, forms chromium-DNA adducts and chromium-DNA cross-links, and disrupts transcriptional activator-co-activator complexes. We have shown previously that exposure of mouse hepatoma Hepa-1 cells to chromate inhibits the induction of the Cyp1a1 and Nqo1 genes by dioxin. Here we have tested the hypothesis that chromium blocks gene expression by interfering with the assembly of productive transcriptional complexes at the promoter of inducible genes. To this end, we have studied the effects of chromium on the expression of genes induced by benzo[a]pyrene (B[a]P), another aryl hydrocarbon receptor agonist, and characterized the disruption of Cyp1a1 transcriptional induction by chromium. Gene expression profiling by using high density microarray analysis revealed that the inhibitory effect of chromium on B[a]Pdependent gene induction was generalized, affecting the induction of over 50 different genes involved in a variety of signaling transduction pathways. The inhibitory effect of chromium on Cyp1a1 transcription was found to depend on the presence of promoter-proximal sequences and not on the cis-acting enhancer sequences that bind the aryl hydrocarbon receptor-aryl hydrocarbon receptor nuclear translocator complex. By using transient reporter assays and chromatin immunoprecipitation analyses, we found that chromium prevented the B[a]P-dependent release of HDAC-1 from Cyp1a1 chromatin and blocked p300 recruitment. These results provide a mechanistic explanation for the observation that chromium inhibits inducible but not constitutive gene expression.
We have shown that dicyanogold(I), [Au(CN)2]- is a common metabolite found in blood and
urine samples of patients treated with different gold based drugs. Some patients have high levels
of gold within their red blood cells (RBCs). Size exclusion and C18 reversed phase
chromatography show that the majority of the gold in RBC lysates is bound to protein, but small
molecules such as dicyanogold(I) and gold-glutathione complexes are also present. Dicyanogold
incubation with red blood cells in vitro leads to a rapid and complete uptake of gold. This uptake
is unaffected by DIDS, an inhibitor of the anion channel, but is blocked by the addition of external
cyanide. Dicyanogold is also readily taken up by H9 cells, a continuous CD4+ cell line. This
uptake is significantly inhibited by N-ethylmaleimide, suggesting a requirement for sulfhydryl
groups. Dicyanogold inhibits the replication of the AIDS virus, HIV, in a cell culture model.
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