Ceruloplasmin injection

In rodents, copper administered by single intraperitoneal or subcutaneous injection is lethal at 3 to 7 mg Cu/kg BW (Table 3.7). Mice died when their drinking water contained 640 mg Cu/L (Table 3.7). In rats, copper accumulation in kidneys and lungs is similar regardless of route of administration (Romeu-Moreno et al. 1994). Concentrations of copper in serum of rats (Rattus sp.) reflect dietary copper concentrations in liver and kidney are directly related to serum Cu and ceruloplasmin (Petering et al. 1977). As serum Cu concentrations rise in rats, levels fall for serum cholesterol, triglycerides, and phospholipids (Petering et al. 1977). 

After 4 injections (8 days), 63% died after 5 injections, 75% died all deaths occurred between days 11 and 35. At day 66, survivors had elevated lung collagen and increased ceruloplasmin (Masaoka et al. 1987)... 

Ceruloplasmin can be detected in the bile (J2), but the amounts found cannot account for more than a very small fraction of the copper in bile. Approximately 50% of the copper in bile is bound to various other proteins, and the rest is probably complexed to smaller organic molecules (H5). Hawke and Holmes (H6) foimd convincing evidence of an enterohepatic circulation of copper. To decide whether copper, once excreted via the bile, could be reabsorbed from the intestine, they cannulated the bile duct of a rat and connected it with a tube to the duodenmn of a second rat. Following intravenous injection of radioactive copper into the first rat, activity could be detected in the blood, bile, and organs of the second rat. Obviously, the Cu excreted via the bile of the first rat was absorbed from the bowel of the recipient animal. 

Fig. 3. The distribution of a single intravenous dose of 1 mg radioactive labeled copper (Cu ) in the various body compartments of a human control. The percentage of the dose in the total plasma compartment, that boimd to ceruloplasmin, that taken up by the liver, and that taken up by the rest of the body are plotted against time following injection.

In vivo, the extent of glycosylation of proteins may be an important controlling factor in their rate of turnover. Removal of the terminal sialic acid residue from such glycoproteins as orosomucoid, fetuin, ceruloplasmin, and thyroglobulin by neuraminidase prior to injection into rats led to increased rates of removal of the modified protein from circulation (256). Removal of both the sialic and galactose residues from ceruloplasmin gave rates similar to those in which the unmodified protein was injected (179,257). 

Serotonin is metabolized to bufotenin, and much of this is excreted in the urine as a glucuronide conjugate [56]. Vindoline and related alkaloids of Catharanthus roseus are extensively metabolized by mammals through the actions of esterases, peroxidases, and P-450 oxidases [57]. Oxidation of vindoline and vinblastine occurs in human serum, catalyzed by ceruloplasmin [58], The major metabolite of yohimbine is 11-hydroxyyohimbine, but the 10-hydroxy derivative is also produced [59], Strychnine injected into rats gives as its major metabolite its 21,22-epoxide, but other epoxidized and hydroxy derivatives are also prodced [60]. Harman is hydroxylated at C-6 by mice [61]. 

Table IV. Increase in Plasma Iron During the First Hour after Injection of Ceruloplasmin or Copper Sulfate...

Figure 15. Effect of feeding 0.75% zinc in the diet on the ceruloplasmin levels in otherwise normal rats. In the lower figure the injection of 100 fjig Cu(II) and 400 fxg iron or both are shown, indicating no restoration by iron alone and partial restoration by copper. Data adapted from Lee and Matrone, Ref. 53.

Morell et al. (1966) observed that a radioactive preparation of asialoceruloplasmin upon injection into rabbits was cleared from the circulation in a matter of minutes, vastly more rapidly than native ceruloplasmin, whose half-life is about 56 hr. In subsequent work (Morell et al., 1968) they observed that the rapid disappearance of the asialoceruloplasmin from the serum was accompanied by an equally rapid accumulation of radioactivity within the liver, specifically in the lysosomal fraction of the parenchymal cells (Gregoriadis et al., 1970). 

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