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Nitrogen oxide-induced autoprotection in isolated rat hepatocytes
Y M Kim1, H Bergonia, J R Lancaster
1Department of Surgery, University of Pittsburgh School of Medicine, PA 15261, USA.
FEBS Letters
|October 30, 1995
Summary
Rat hepatocytes develop resistance to nitrogen oxide toxicity after low-dose exposure, involving protective proteins and increased ferritin. This inducible defense mechanism also confers cross-resistance to hydrogen peroxide (H2O2) damage.
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Nitrogen oxides (NOx) and reactive oxygen species (ROS) can cause cellular damage.
- Hepatocytes play a crucial role in detoxification and are susceptible to oxidative stress.
Purpose of the Study:
- To investigate the inducible protective mechanisms in rat hepatocytes against nitrogen oxide toxicity.
- To elucidate the molecular players involved in this protective response.
Main Methods:
- Hepatocytes were pretreated with low-dose nitrogen oxide (SNAP or NOS induction).
- Cells were subsequently exposed to higher doses of SNAP or hydrogen peroxide (H2O2).
- Levels of aconitase, ferritin, and non-heme iron-NO EPR signals were measured. Effects of cycloheximide and tin-protoporphyrin (SnPP) were assessed.
Main Results:
- Low-dose nitrogen oxide pretreatment conferred resistance to subsequent high-dose SNAP-induced toxicity.
- This protection was associated with decreased aconitase activity and mitochondrial electron transfer.
- Increased ferritin levels and non-heme iron-NO EPR signals were observed.
- Cycloheximide blocked the development of resistance, indicating protein synthesis.
- Tin-protoporphyrin (SnPP) inhibited protection, suggesting roles for heme oxygenase (hsp32) and/or guanylyl cyclase (GC).
- Cross-resistance to H2O2 killing was also observed and prevented by cycloheximide and SnPP.
Conclusions:
- Hepatocytes possess inducible protective mechanisms against nitrogen oxide toxicity.
- These mechanisms involve the upregulation of specific proteins and alterations in iron metabolism.
- The observed cross-resistance suggests a common pathway for protection against both nitrogen oxide and reactive oxygen species.