INDUCTION OF HEPATIC HEME OXYGENASE-1 AND FERRITIN IN RATS BY CANCER CHEMOPREVENTIVE DITHIOLETHIONES

Treatment of rats with the cancer chemopreventive agent 1,2-dithiole-3 -thione (D3T) resulted in a significant increase in hepatic heme oxyge nase (HO) activity, which corresponded to increased protein levels of HO-1. Upon further analysis of proteins related to heme metabolism, th e level of ferritin, the major iron storage protein in liver, was also found to be elevated, Diminished levels of intracellular free iron we re monitored by EPR spectroscopy at times after administration of D3T that suggested that increased ferritin content sequesters intracellula r 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 fo und. The inductions of FL and FH, but not HO-1, were sensitive to cycl oheximide, suggesting that in vivo these genes are regulated by distin ct D3T-responsive transcriptional mechanisms. The known protective rol es for induced HO-1 and ferritin in cellular stress have been suggeste d to include increased levels of the antioxidant bilirubin and enhance d sequestration of intracellular iron into ferritin, which can effecti vely 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 media ted, in part, by the induction of HO-1, FL and FH.