Iron and the liver Acute and long-term effects of iron-loading on hepatic haem metabolism

Abstract

We have determined the dose-response curves (100-900 mg of Fe/kg body wt.) and the time course over 84 days for the effects of a single injection of iron-dextran on rat hepatic 5-aminolaevulinate synthetase, cytochrome P-450, iron content, and GSH (reduced glutathione). Porphyrins in liver and urine have also been measured. (1) At 2 days after treatment, a dose of 500 mg of Fe/kg produced a 20-fold increase in iron concentration, which was maintained for 14 days. Total hepatic iron remained constant over 63 days, falling slightly by 84 days. (2) The activity of 5-aminolaevulinate synthetase was maximally increased (6-fold) 12-24 h after iron treatment. By 48 h the activity fell to less than twice the control value and thereafter remained slightly above the control value (1.1-1.5-fold) until 84 days after iron treatment. Liver GSH concentrations were unaffected by iron. Porphyrins in liver and urine were either unchanged or decreased. (3) Hepatic cytochrome P-450 decreased after iron treatment to a minimum (63% of control) at 48 h after iron administration and gradually returned to the control value by 28 days. (4) Iron-dextran potentiated 2 allyl-2-isopropyl-acetamide-induced synthesis of hepatic 5-aminolaevulinate. Potentiation occurred if the drug was given at the same time or 36 h after iron administration, but did not occur if the drug was given 14 or 64 days after iron administration. (5) The results are discussed in relation to proposed mechanisms for the effects of iron on hepatic haem metabolism.

Iron and the liver: acute effects of iron-loading on hepatic heme synthesis of rats. Role of decreased activity of 5-aminolevulinate dehydrase.

“…However, others have reported no effect (7) or activation (8) of the decarboxylase by ionic iron. We have also failed to find evidence for a decrease in activity of uroporphyrinogen decarboxylase in iron-loaded liver (1,9).…”

“…patic 5-aminolevulinate (ALA)' synthase, the rate-limiting enzyme in hepatic heme biosynthesis (1). The peak of the increase (four-to sixfold above control) occurs 12-24 h after treatment; by 48 h the activity of ALA synthase decreases to 1.5-fold greater than control, and persists for several weeks (1,2).…”

“…The peak of the increase (four-to sixfold above control) occurs 12-24 h after treatment; by 48 h the activity of ALA synthase decreases to 1.5-fold greater than control, and persists for several weeks (1,2). According to current concepts, a regulatory heme pool exerts endproduct negative feedback control on synthesis of ALA synthase (for recent reviews, see refs.…”

Malondialdehyde and 4-hydroxynonenal protein adducts in plasma and liver of rats with iron overload.

“…The mechanisms responsible for the development ofhepatocellular injury in patients with hemochromatosis are not known, but a direct correlation between hepatic iron and hepatic fibrosis has been demonstrated (3,4). Because lipid peroxidation is known to be catalyzed by iron, enhanced lipid peroxidation has been proposed as an initial step by which excess iron causes cellular injury (1,5). This proposal is supported by results from animal studies and in vitro models (6)(7)(8)(9)(10)(11)(12).…”

“…Animals were weighed weekly and the diet ofthe control animals adjusted to maintain similar growth rates to the carbonyl iron-fed animals. At 5 wk, animals were anesthetized by an intramuscular injection of ketamine (100 mg/kg), zylazine (2 mg/kg), and acepromazine (2.5 mg/kg) and then killed by cardiac puncture and their livers promptly removed. A portion was rinsed in ice-cold PBS and immediately frozen in liquid nitrogen; the remainder was fixed in 10% formalin for Perls' prussian blue staining.…”