Biochemical lesions in copper-deficient rats caused by secondary iron deficiency. Derangement of protein synthesis and impairment of energy metabolism

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Abstract
Severe Cu deficiency was induced in rats by rearing nursing dams and their offsprings on a semisynthetic diet comprising all the requisite nutrients and trace metals except Cu. The Cu-deprived rats exhibited growth retardation, severe anemia, loss of ceruloplasmin, decrease of cytochrome oxidase, accumulation of salt-soluble collagen and a drastic decrease in Fe in plasma and liver. Apart from these characteristic signs of deficiency, a marked inhibition of protein synthesis occurred in vivo and in cell free liver preparations. The curtailed ability to carry out endogenously coded amino acid incorporation into protein contrasted with the unimpaired poly(U)-acid-directed phenylalanine polymerization. This inhibition pattern and the attendant disaggregation of the liver polyribosomes, suggested that the primary biosynthetic lesion was located at the stage of peptide-chain initiation. There was a pronounced depletion of the hepatic ATP content associated with a parallel depression of mitochondrial respiration and an enhancement of ATPase activity. Supplementation of the Cu-deficient diet with a 2- to 4-fold excess of Fe (relative to the standard diet) prevented growth retardation and anemia and restored normal energy metabolism and unimpaired protein-synthesizing capacity. These disturbances were primarily determined by the secondary Fe deficiency; similar alterations occurred in rats maintained on a Cu-sufficient but Fe deficient diet. The Fe-fortified diet failed to reverse the other signs of Cu deficiency, i.e., the loss of ceruloplasmin, the diminished rate of cytochrome oxidase and the increase of soluble collagen. The interrelations between the various biochemical lesions induced by deprivation of Cu or Fe are discussed and the possible role of ATP depletion in determining the derangement of protein synthesis is considered.