Compound-specific adaptation of hepatoma cell lines to toxic iron.

Cellular adaptation to excess iron (Fe) is a major determinant to protect tissues from toxicity. The adaptation of hepatoma cell lines following exposure to toxic levels of Fe compounds was studied. A dose- and time-dependent induction of toxicity was observed that was strictly compound-specific. Similar ranging orders of toxicity, i.e. iron chloride >iron sulfate >iron citrate, were observed in four human hepatoma cell lines. Long-term cultivation of HepG2 cells in 10 mM iron citrate resulted in a resistant cell line that displayed high proliferation rates for several months. Resistant cells showed increased viability at iron citrate concentrations ranging from 5-15 mM, while exposition to iron chloride or iron sulfate induced high rates of toxicity similar to parental cells. Resistance was not due to decreased Fe uptake/storage since high intracellular Fe levels were observed. A broad range of modulated gene expression was associated with short- and long-term iron citrate exposition; however, after weaning of resistant cells, re-exposition to Fe induced a similar level of toxicity as observed in parental cells suggesting that a transient adaptation of gene expression was mounted. The results indicate that, depending on the nature of the Fe compound, a specific level of toxicity is induced in hepatic cells which however can be overcome by establishment of resistance.