Liver AP-1 activation due to carbon tetrachloride is potentiated by 1,2-dibromoethane but is inhibited by alpha-tocopherol or gadolinium chloride.
Experimental acute intoxication by prooxidant haloalkanes produces marked stimulation of hepatic lipid peroxidation and cytolysis, which is followed by tissue regeneration. Our aim was to clarify the role of oxidative imbalance in the activation of the redox-sensitive transcription factor, activator protein-1 (AP-1), which is involved in tissue repair. Rats were poisoned with a very low concentration of carbon tetrachloride, given alone or in combination with another hepatotoxin, 1,2-dibromoethane, to provide varying extents of oxidative damage. The level of AP-1-DNA binding was analyzed by electrophoretic mobility shift assay on liver extracts, obtained from rats killed 6 h after poisoning. Stimulation of lipid peroxidation and AP-1 upregulation were already established when the hepatic damage due to carbon tetrachloride +/-1,2-dibromoethane was beginning to appear. Rat supplementation with the antioxidant vitamin E completely inhibited AP-1 upregulation, thus supporting a causative role of membrane lipid oxidation in the observed modulation of the transcription factor. Moreover, activation of Kupffer cells appears to be a crucial step in the increased AP-1 binding to DNA, the latter being largely prevented by gadolinium chloride, a macrophage-specific inhibitor.
Camandola
S
S
Department of Experimental Medicine and Oncology, University of Turin, Italy.
Aragno
M
M
Cutrin
J C
JC
Tamagno
E
E
Danni
O
O
Chiarpotto
E
E
Parola
M
M
Leonarduzzi
G
G
Biasi
F
F
Poli
G
G
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity*; D004347:Drug Interactions; D015946:Ethylene Dibromide / Q000008:administration & dosage / Q000633:toxicity*; D005682:Gadolinium / Q000494:pharmacology; D066298:In Vitro Techniques; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D018808:Transcription Factor AP-1; D014810:Vitamin E; D015946:Ethylene Dibromide; D005682:Gadolinium; D002251:Carbon Tetrachloride; C038958:gadolinium chloride