Iron mobilisation and cellular protection by a new synthetic chelator O-Trensox.
We tested a new synthetic, 8-hydroxyquinoline-based, hexadentate iron chelator, O-Trensox and compared it with desferrioxamine B (DFO). Iron mobilisation was evaluated: (i) in vitro by using ferritin and haemosiderin; DFO mobilised iron much more rapidly from ferritin at pH 7.4 than did O-Trensox, whereas at pH 4, ferritin and haemosiderin iron mobilisation was very similar with both chelators; (ii) in vitro by using cultured rat hepatocytes which had been loaded with 55Fe-ferritin; here DFO was slightly more effective after 100 hr than O-Trensox; (iii) in vivo administration i.p. to rats which had been iron-loaded with iron dextran; O-Trensox mobilised 51.5% of hepatic iron over two weeks compared to 48.8% for DFO. We also demonstrated the effect of O-Trensox in decreasing the entry of 55Fe citrate into hepatocyte cultures. The protective effect of O-Trensox against iron toxicity induced in hepatocyte cultures by ferric citrate was shown by decreased release of the enzymes lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotranferase (ALT) from the cultures and, using electron paramagnetic resonance (EPR) measurements, decreased production of lipid radicals. O-Trensox was more effective than DFO in quenching hydroxyl radicals in an acellular system.
INSERM U 49, Unite de Recherches Hepatologiques, Rennes, France.
N
N
Rakba
F
F
Aouad
C
C
Henry
C
C
Caris
I
I
Morel
P
P
Baret
J L
JL
Pierre
P
P
Brissot
R J
RJ
Ward
G
G
Lescoat
R R
RR
Crichton
D000818:Animals; D002478:Cells, Cultured; D003676:Deferoxamine / Q000378:metabolism / Q000494:pharmacology; D005021:Ethylamines / Q000378:metabolism / Q000494:pharmacology*; D005290:Ferric Compounds / Q000633:toxicity; D005293:Ferritins / Q000378:metabolism / Q000633:toxicity; D006485:Hemosiderin / Q000378:metabolism; D006912:Hydroxyquinolines / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism* / Q000633:toxicity; D007502:Iron Chelating Agents / Q000378:metabolism / Q000494:pharmacology*; D007505:Iron-Dextran Complex / Q000633:toxicity; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D005021:Ethylamines; D005290:Ferric Compounds; D006912:Hydroxyquinolines; D007502:Iron Chelating Agents; C097548:trensox; C025314:ferric citrate; D007505:Iron-Dextran Complex; D005293:Ferritins; D006485:Hemosiderin; D007501:Iron; D003676:Deferoxamine