Molecular basis of hexavalent chromium carcinogenicity: effect on gene expression.

The carcinogenicity of chromium(VI) compounds is explained in terms of the "uptake-reduction" model. According to this model, chromium (VI) enters cells as the anionic tetrahedral species chromate, CrO4(2-), using normal cellular anion transport systems, such as the sulfate transport system. Redox-active enzymes and small molecules reduce chromium (VI) intracellularly and produce "reactive intermediates" capable of damaging cellular constituents. DNA is presumed to be a critical target within the cell; however, chromium (VI) itself is unreactive toward DNA under physiological conditions in vitro. Thus, the ability of chromium(VI) to damage DNA depends on the presence of cellular components capable of producing putative DNA-damaging agents, such as chromium(VI) thioester, chromium(V), chromium(IV), chromium(III), thiyl radical and hydroxyl radical, upon reaction with the chromium(VI). The exact nature of the DNA damage will be strongly dependent on the reactive intermediates produced by cellular components and systems active in chromium(VI) metabolism. The chromium(VI)-induced DNA damage disrupts the normal functioning of DNA in critical cellular processes, including transcription and replication. The effect of chromium(VI)-induced DNA damage on the function of DNA as a template for transcription has been examined in chick embryo liver in vivo. Chromium(VI) induced DNA-protein and DNA interstrand cross-links and suppressed the induction of 5-aminolevulinic acid synthase and cytochrome P-450 mRNA by porphyrinogenic drugs. In contrast, chromium(VI) increased the basal steady-state mRNA levels of these two inducible genes, but had no effect on the steady-state mRNA levels of the constitutive genes, beta-actin, conalbumin and albumin. Nuclear "run-off" transcription experiments showed that the effect of chromium(VI) on the steady-state levels of basal and drug-inducible 5-aminolevulinic acid synthase mRNA was principally the result of changes in the transcription rate of the 5-aminolevulinic acid synthase gene. Chromium(VI)-induced changes in gene expression correlated with the presence of DNA interstrand and DNA-protein cross-links, suggesting that chromium(VI)-induced DNA lesions lead to changes in expression of the targeted genes.