TY - JOUR
T1 - Induction of hepatic heme oxygenase-1 and ferritin in rats by cancer chemopreventive dithiolethiones
AU - Primiano, Thomas
AU - Kensler, Thomas W.
AU - Kuppusamy, Periannan
AU - Zweier, Jay L.
AU - Sutter, Thomas R.
N1 - Funding Information:
This work was supported by Grants CA 39416 and CA44530 from the National Institutes of Health, by NIEHS Center Grant ES 03819 and by a Johns Hopkins University School of Hygiene and Public Health Faculty Development Award (TRS). TP was supported by NIEHS Training Grant ES 07141 and American Institute for Cancer Research Grant 95A119. The authors wish to thank Patricia Egner and Patrick Dolan for outstanding technical assistance.
PY - 1996/11
Y1 - 1996/11
N2 - 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.
AB - 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.
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U2 - 10.1093/carcin/17.11.2291
DO - 10.1093/carcin/17.11.2291
M3 - Article
C2 - 8968040
AN - SCOPUS:0029830816
SN - 0143-3334
VL - 17
SP - 2291
EP - 2296
JO - Carcinogenesis
JF - Carcinogenesis
IS - 11
ER -