Release of free, redox-active iron in the liver and DNA oxidative damage following phenylhydrazine intoxication.
Following the subchronic intoxication of rats with phenylhydrazine, resulting in marked anemia, reticulocytosis, methemoglobinemia and increased hemocatheresis, the hepatic content of total iron was increased, as was hepatic ferritin and its saturation by iron. A striking increase (approximately 7-fold) was also observed in free iron which appeared to be redox-active. The increase in liver free iron involved the hepatocellular component of the liver. Since DNA is one of the cellular targets of redox active iron, liver DNA from phenylhydrazine-treated rats was analyzed by electrophoresis and found to be markedly fragmented. Experiments with isolated hepatocytes in culture or in suspension challenged with phenylhydrazine or Fe-nitrilotriacetate strongly suggested that the DNA damage was due to reactive iron rather than to the hepatic metabolism of phenylhydrazine. The levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), a specific marker of oxidative DNA damage, were significantly higher in phenylhydrazine-treated rats as compared to untreated controls. The prolongation of phenylhydrazine treatment over a period of 6 weeks resulted in a persistent damage to DNA and in phenotypic changes such as an increase in hepatocyte gamma-glutamyl transpeptidase (gamma-GT, EC 2.3.2.2) activity. Possible relationships between iron overload, iron release, DNA damage and tumor initiation are discussed.
Ferrali
M
M
Istituto di Patologia Generale dell'Università di Siena, Italy.
Signorini
C
C
Sugherini
L
L
Pompella
A
A
Lodovici
M
M
Caciotti
B
B
Ciccoli
L
L
Comporti
M
M
D000818:Animals; D004249:DNA Damage; D053938:DNA Fragmentation; D004912:Erythrocytes / Q000187:drug effects; D006651:Histocytochemistry; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000139:chemically induced*; D015227:Lipid Peroxidation; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D010659:Phenylhydrazines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000032:analysis
D010659:Phenylhydrazines; C030299:phenylhydrazine; D007501:Iron; D005723:gamma-Glutamyltransferase