The feeding of diets enriched with (3,5,5-trimethylhexanoyl)ferrocene (TMH-
ferrocene) has been shown recently to produce a severe experimental
iron overload in rats and has been considered as an adequate animal model for hereditary
haemochromatosis in humans. We synthesized three 59Fe-labelled
ferrocene compounds with different lipophilic characters (
ferrocene, TMH-
ferrocene, and 1,1'-bis(3,5,5-trimethylhexanoyl)
ferrocene [(TMH)2-
ferrocene]) and studied the metabolism of
iron from these compounds in comparison with the hydrophilic
ferrous sulphate in rats with
iron deficiency, and normal and increased
iron stores. The bioavailability of
iron from TMH-
ferrocene (whole body retention, 48% from a 5 mg Fe dose) was twice as high as from
ferrocene and six times higher than from (TMH)2-ferrocene and
ferrous sulphate. In contrast to the well-known
iron salts (
ferrous sulphate), the intestinal absorption of TMH-
ferrocene iron was independent from the dose (1 or 5 mg Fe) and similar in
iron-deficient and
iron-loaded rats, indicating that the intestinal absorption of the TMH-
ferrocene is not regulated by the body
iron stores. After intestinal absorption, TMH-
ferrocene iron in the portal blood is transported to the liver independently from
transferrin. In contrast to absorbed
ferrocene,
iron from TMH-
ferrocene is almost completely released from the
hydrocarbon moiety within the liver. Depending on the body
iron stores, TMH-
ferrocene iron is then incorporated preferentially into haemoglobin (
iron-deficient rats) or added to the
iron stores in the liver (
iron-loaded rats). A transient storage of the 59Fe-label in fat tissue was observed only from oral
ferrocene but not from TMH-
ferrocene. Due to the outstandingly high bioavailability of TMH-
ferrocene, the chronic feeding of this compound resulted in a fast and progressive
iron overload in rats (liver
iron: 16.9 mg Fe/g wet weight after 10 weeks of feeding a diet containing 0.5% TMH-
ferrocene), and can be regarded as the best characterized and most useful animal model for severe hepatocellular
iron overload in humans.