Plasma protein turnover

The body contains approx. 14,000 g protein in total. There is a 24-hour turnover of 600-700 g of the amino acid pool. The musculature has the highest absolute rate of protein synthesis. The protein synthesized here is retained for exclusive use in the muscles. In relation to its weight, the liver generates more protein than the musculature. The synthesis rate in the liver amounts to 120 g/ day, whereby 70-80% of these proteins are released by the hepatocytes, so that only 20-30% remain available for their own use. Plasma protein turnover is 25 g/day, that of the total tissue protein approx. 150 g/day. Amino acid turnover and protein synthesis proceed rapidly and continuously. 

The mechanism of mercury excretion in the bile is unknown. Binding to glutathione and cysteine has been demonstrated in rodents (Refsvik and Norseth, 1975). The excretion through the intestinal mucosa may be related to the plasma protein turnover. The relative importance of the main excretory routes - by feces and by urine - is dose-dependent -with higher doses, a larger portion is excreted by urine (Lomholt, 1928). 

A certain elimination of methyl mercury may occur in other parts in the intestinal canal and may possibly be linked with the plasma protein turnover in the intestinal tract. An important factor in the excretion by the fecal route is the enterohepatic circulation of methyl mercury. Methyl mercury excreted into the bile or through the intestinal mucosa is likely to be reabsorbed unless it is decomposed in the gut to inorganic mercury, which has been proven to occur due to the microbiological activity in the gut of the mouse (Nakamura et al., 1977), the rat and man (Rowland et al., 1977). 

Because of the relative ease with which they can be obtained, plasma proteins have been smdied extensively in both humans and animals. Considerable information is available about the biosynthesis, turnover, strucmre, and functions of the major plasma proteins. Alterations of their amounts and of their metabolism in many disease states have also been investigated. In recent years, many of the genes for plasma proteins have been cloned and their stmcmres determined. 

The preparation of antibodies specific for the individual plasma proteins has greatly facilitated their smdy, allowing the precipitation and isolation of pure proteins from the complex mixmre present in tissues or plasma. In addition, the use of isotopes has made possible the determination of their pathways of biosynthesis and of their turnover rates in plasma. 

Amino Acids Amino acids that enter the liver follow several important metabolic routes (Fig. 23-14). (1) They are precursors for protein synthesis, a process discussed in Chapter 27. The liver constantly renews its own proteins, which have a relatively high turnover rate (average half-life of only a few days), and is also the site of biosynthesis of most plasma proteins. (2) Alternatively amino acids pass in the bloodstream to other organs, to be used in the synthesis of tissue proteins. (3) Other amino acids are precursors in the biosynthesis of nucleotides, hormones, and other nitrogenous compounds in the liver and other tissues. 

The majority of body iron is not chelatable (iron from cytochromes and hemoglobin). There are two major pools of chelatable iron by DFO (19). The first is that delivered from the breakdown of red cells by macrophages. DFO competes with transferrin for iron released from macrophages. DFO will also compete with other plasma proteins for this iron, when transferrin becomes saturated in iron overload. The quantity of chelatable iron from this turnover is 20mg/day in healthy individuals and iron chelated from this pool is excreted in the urine (19). The second major pool of iron available to DFO is derived from the breakdown of ferritin and hemosiderin. The ferritin is catabolized every 72 hours in hepatocytes, predominantly within lysosomes (I). DFO can chelate iron that remains within lysosomes shortly after ferritin catabolism or once this iron reaches a dynamic, transiently chelatable, cytosolic low-molecular-weight iron pool (20). Cellular iron status, the rate of uptake of exogenous iron, and the rate of ferritin catabolism are influent on the level of a labile iron pool (21). Excess ferritin and... 

Contemporary clinical medicine pays careful attention to the hydration state of the extracellular space, but not enough to cellular hydration probably because of the lack of routinely applicable techniques for the assessment of cell volume in patients. However, it should be kept in mind that cell hydration is determined primarily by the activity of ion and substrate transporting systems in the plasma membrane, and, to a minor extent, by the hydration state of the extracellular space. The role of cell hydration in regulating protein turnover is an important one, partly because it has a direct bearing on the problem of the pathogenesis of protein-catabolic states in the severely ill. As emphasized earlier, a decrease in cell hydration inhibits protein... 

Each tissue, including the bloodstream, has a free amino acid pool. This amounts to a total of about 100 g. By far the largest fraction, 50-80%, is located in muscle. Kidney accounts for about 4%, liver for 10%, and the bloodstream another 4%. Glutamine and glutamate are major components of such pools. Free amino acid pools are in equilibrium with tissue protein. Tissue proteins are in a constant state of turnover, that is, biosynthesis and degradation from and to free amino acids. Only plasma proteins, which are largely synthesized in the liver, are not in equilibrium with the plasma free amino acid pool. 

Whereas some characteristics and properties of CETP have been defined, many questions remain to be answered. We do not yet know the origin of the protein, the nature of factors that regulate its concentration in the plasma, its turnover time, the origin and metabolism of its inhibitor, or even the fundamental question of its physiological role in the plasma. A great deal more investigation into CETP is clearly warranted. 

The concentration of amino acids in the blood of patients with liver disease is often elevated. This change is, in part, attributable to a significantly increased rate of protein turnover (general catabolic effect seen in severely ill patients) as well as to impaired amino acid uptake by the diseased liver. It is unlikely that the increased levels are due to degradation of liver protein and the subsequent release of amino acids from the failing hepatocyte into the blood. This is true because the total protein content of the liver is only approximately 300 g. To account for the elevated amino acid levels in the blood, the entire protein content of the liver would have to be degraded within 6 to 8 hours to account for the increased protein turnover rates found. Because 18 to 20 times more protein is present in skeletal muscle (greater mass), the muscle is probably the major source of the elevated plasma levels of amino acids seen in catabolic states such as cirrhosis of the liver. 

Thrombotic complications are frequently encountered when blood is exposed to the surfaces of hemodialysis devices, heart-lung machines, arterial grafts, artificial heart components and other prosthetic devices. The blood platelets are particularly vulnerable to these adverse effects which may include a decrease in platelet count, shortened platelet survival and attendant higher platelet turnover, and altered platelet function. However the interaction of platelets with an artificial surface exposed to blood must be preceded by the interaction of the molecular components of plasma, particularly the plasma proteins, with the surface (1,2). This is due to the prepon-... 

The dynamic process in which body proteins are continuously hydrolyzed and resynthesized is called protein turnover. The turnover rate, or life expectancy, of body proteins is a measure of how fast the proteins are broken down and resynthesized. The turnover rate is usually expressed as a half-life. The use of radioactive amino acids has enabled researchers to estimate half-lives by measuring the exchange rate between body proteins and the amino acid pool. For example, the half-life of liver proteins is about 10 days. This means that over a 10-day period, half the proteins in the liver are hydrolyzed to amino acids and replaced by equivalent proteins. Plasma proteins also have a half-life of about 10 days, hemoglobin about 120 days, and muscle protein about 180 days. The half-life of collagen, a protein of connective tissue, is considerably longer—some estimates are as high as 1000 days. Other proteins, particularly enzyme and polypeptide hormones, have much shorter half-lives of only a few minutes. Once it is released from the pancreas, insulin has a half-life estimated to be only 7-10 minutes. 

Studies by Lim et al. [22] on the distribution and kinetics of intravenously administered Cr have been used to establish a functional physiological model. Initially, 95% of the chromium is bound to plasma protein and 5% is free. The free chromium is eliminated by the kidney with a half-life of 3.5 hr. The bound fraction is in equilibrium with three tissue compartments, which represent the total chromium in the body. One of the compartments is small (0.13 p.g of Cr) with a turnover rate on the order of minutes, another compartment is about six times larger (0.8 ig of Cr) with a turnover rate on the order of 1 or 2 days, while the largest compartment (24.4 p.g of Cr) has an influx half-life of 4.2 days and efflux half-life of 315 days [9,22]. 

In an attempt to exclude the use of urea from protein turnover measurements, [ N]lysine has been infused intravenously until the free lysine in the plasma achieved plateau labelling [431]. From the lysine flux, and its mean representation in all body proteins, turnover rates were calculated in a manner analogous to that used in radioactive amino acid studies [432]. In addition, serial muscle biopsies taken 14—16h apart when plasma [ N] lysine plateau conditions prevailed, enabled muscle protein turnover rate to be calculated. This was found to account for 53% of whole body protein turnover. 

Finally, both constant infusion and pulse label techniques using isotopic labels to estimate whole body protein turnover share the common premise that there is a homogeneous metabolic nitrogen pool of which the plasma constitutes an integral part. That this is in fact an oversimplification, has been shown from animal studies [438]. Despite these, and other objections, work will continue in the search for a reliable method for the estimation of protein synthesis, catabolism and turnover in man. To the clinician such a method would provide information about nitrogen loss from the body resulting from malnutrition, postoperative trauma, burns or severe infection and perhaps more importantly an indication of the success or otherwise of the specific therapeutic regime implemented. 

As can be expected, plasma proteins have a rapid turnover. Isotopic studies have shown that the half-life of a plasma protein molecule is about 15 days, and that plasma proteins are an important source of proteins in tissues. Animals put on a protein-free diet maintain a perfect nitrogen balance for 3 months when plasma is administered to them. During starvation, plasma proteins remain intact for a long time, in spite of rapid use of tissue proteins. These facts explain the salutary effects of plasma proteins administered for chronic malnutrition, or to surgical patients who cannot be fed. Since there is no correlation between the rate of plasma and tissue protein use in malnutrition, serum protein determination is of little value in estimating a patient s nutritional status. 

These data indicate that the turnover of RBP in vivo is quite rapid, with a fairly high body synthetic (production) rate for a protein of such low plasma concentration. This rapid turnover rate underlies the potential usefulness of RBP measurements in helping to assess the functional state of the liver in patients with hepatic disease, or the nutritional status of patients with borderline or actual malnutrition (see discussion below under clinical studies). It is of interest to compare the turnover of RBP with that of other plasma proteins. It has been pointed out (F. R. Smith et al., 1975) that the respective half-lives (in days) and synthetic rates (in milligrams per kilogram per day) in normal adult human subjects are approximately 0.5 and 5 for RBP 2-3 and 8-9 for TTR (Vahlquist et al., 1973 Socolow et al., 1965) and 14 and 200 for albumin (Beeken et al., 1962). 

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