Treatment of rats with the
cancer chemopreventive agent
1,2-dithiole-3-thione (D3T) resulted in a significant increase in hepatic
heme oxygenase (HO) activity, which corresponded to increased
protein levels of HO-1. Upon further analysis of
proteins related to
heme metabolism, the level of
ferritin, the major
iron storage
protein in liver, was also found to be elevated. Diminished levels of intracellular free
iron were monitored by EPR spectroscopy at times after administration of D3T that suggested that increased
ferritin content sequesters intracellular
iron. The increased levels of
protein were associated with increased levels of steady-state
RNA of HO-1 and the light (FL) and heavy (FH) subunits of
ferritin. A direct relationship between enhanced rates of gene transcription and elevated levels of HO-1 and
ferritin RNA was found. The inductions of FL and FH, but not HO-1, were sensitive to
cycloheximide, suggesting that in vivo these genes are regulated by distinct D3T-responsive transcriptional mechanisms. The known protective roles for induced HO-1 and
ferritin in cellular stress have been suggested to include increased levels of the
antioxidant bilirubin and enhanced sequestration of intracellular
iron into
ferritin, which can effectively reduce
iron-mediated reactive
oxygen generation. Thus, protective actions of D3T against the cytotoxic and carcinogenic consequences of chemicals that exert electrophilic or oxidative stresses may be mediated, in part, by the induction of HO-1, FL and FH.