Decreased cytochrome p450 and increased porphyrin concentrations in the livers of rats on a low iron diet given a single dose of desferrioxamine

The efficacy of the iron chelator desferrioxamine at a site of action in the liver was investigated. A single dose given to 48 hr starved male rats (1.56 m-moles/kg, i.p.) caused a time dependent decrease in liver ferritin iron concentrations to about 60 per cent of control values 4 to 8 hr after dosing. Concurrently with the decrease in ferritin iron levels, there was a small accumulation of porphyrins in the liver. By keeping male rats on a low iron diet for 10 days followed by 48 hr starvation, liver ferritin iron concentrations were reduced to about 5 per cent of control values. Administration of desferrioxamine to these animals caused a further decrease in liver ferritin iron levels and a marked increase in the accumulation of porphyrins in the liver. After 30 days on a low iron diet, liver ferritin iron could no longer be detected. Blood haematocrits and haemoglobin levels were severely depressed. Liver cytochrome b 5 and P450 values were similar to controls. In these animals desferrioxamine caused a substantial time dependent increase in the porphyrin content of the liver and a decrease in cytochrome P450 levels. Cytochrome b 5 concentrations were not significantly affected. It was suggested that these results were consistent with desferrioxamine blocking hepatic haem synthesis by making iron unavailable for inclusion into protoporphyrin at the ferrochelatase step. Relative to control animals, hepatic mitochondrial 5-aminolevulinic acid synthetase was significantly depressed in rats kept for 10 or 30 days on the low iron diet. Administration of desferrioxamine caused no marked increase in 5-aminolevulinic acid synthetase activities in either group of rats in the 24 hr after dosing. It was concluded that in addition to haem, iron may play a regulatory role in controlling the activity of 5-aminolevulinic acid synthetase.