Comparison of the subacute toxicity and efficacy of 3-hydroxypyridin-4-one iron chelators in overloaded and nonoverloaded mice.
Five orally effective iron chelators of the 3-hydroxypyridin-4-one series have been administered intraperitoneally to iron-overloaded and nonoverloaded male mice at a dose of 200 mg/kg/24 h for a total of 60 days to investigate the effect on iron loading and toxicity. There was a significant reduction in hepatic iron at the end of the study in the iron-overloaded mice with all compounds studied using chemical iron quantitation (P less than .001) and with Perls' stain (P less than .01). Liver iron removal with the hydroxypyridinones ranged from 37% with CP20 to 63% with CP51, compared with 46% removal for desferrioxamine (DFO). There was no significant reduction in splenic or cardiac iron with any chelator. There were no deaths in iron-overloaded animals receiving any of the hydroxypyridin-4-ones, but significantly more deaths in the nonoverloaded groups as a whole (P less than .03). No weight loss was observed with any chelator. Significant reductions in hemoglobin and white cell count were observed with CP20(L1). No histologic abnormalities of kidney, spleen, bone marrow, or stifle joints were observed. Intracytoplasmic inclusion bodies were observed in the centrilobular hepatocytes of animals administered each of the hydroxypyridin-4-ones, while the DFO-treated and control groups showed no such changes.
Porter
J B
JB
Department of Clinical Haematology, University College and Middlesex School of Medicine, London, UK.
Hoyes
K P
KP
Abeysinghe
R D
RD
Brooks
P N
PN
Huehns
E R
ER
Hider
R C
RC
D000818:Animals; D003676:Deferoxamine / Q000494:pharmacology; D004906:Erythrocyte Count / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism; D007502:Iron Chelating Agents / Q000633:toxicity*; D007958:Leukocyte Count / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009928:Organ Specificity; D011728:Pyridones / Q000633:toxicity*; D013329:Structure-Activity Relationship
D006454:Hemoglobins; D007502:Iron Chelating Agents; D011728:Pyridones; C020366:3-hydroxy-4-pyridone; D003676:Deferoxamine