Hypoxia inducible factor-1 alpha-independent suppression of aryl hydrocarbon receptor-regulated genes by nickel.

Aryl hydrocarbon receptor (AhR)-dependent enzymes are involved in the biotransformation of harmful xenobiotics into more easily excretable metabolites. Cross-talk between the AhR pathway and the hypoxia inducible factor-1alpha (HIF-1alpha) pathway has been demonstrated previously, although the mechanism remains unclear and quite controversial. Because nickel is known to mimic hypoxia, we investigated the effects of short-term nickel exposure on AhR-dependent gene expression. Gene-chip analysis identified several AhR-dependent genes that are suppressed by exposure to nickel. Using Northern blots, we then confirmed that nickel can down-regulate both the basal and benzo[a]pyrene-inducible expression of AhR-dependent genes in mouse and human cell lines. Using a HIF-1alpha knockout cell line and 3-[2-[4-(bis-(4-fluorophenyl) methylene]-1-piperidinyl)ethyl]-2,3-dihydro-2-thioxo-4(1H)quinazolinone (R59949), which blocks HIF-1alpha protein accumulation, we show HIF-1alpha-independent suppression of AhR-dependent genes by nickel. Desferrioxamine and hypoxia were also able to suppress the basal and inducible expression levels of AhR-regulated genes. Finally, dimethyloxalylglycine, an inhibitor of Fe(II)- and 2-oxoglutarate-dependent dioxygenases also inhibited AhR-dependent expression in a HIF-1alpha-independent manner. Our data suggest that an Fe(II)-, oxoglutarate-, and oxygen-dependent enzyme may directly or indirectly be involved in the regulation of AhR-dependent transcriptional activity by nickel and other hypoxia-mimicking agents.