Liver plasma protein synthesis

Miller LL, Bly CG, Watson ML, Bale WF (1951) The dominant role of the liver in plasma protein synthesis a direct study of the isolated perfused rat liver with the aid of lysine-epsilon-C14. J Exp Med 94(5) 431 53... 

In considering how L-tryptophan can affect various organs, it is appropriate to review how it affects protein synthesis in specific organs. In addition to reports that tryptophan stimulates hepatic and plasma protein synthesis as described in Chapter 4, it has also been reported that tryptophan stimulates protein synthesis in other organs. These studies, other than in liver, are cited in this section. 

Haft, D. E., P. S. Roheim, A. White, and H. A. Eder Plasma lipoprotein metabolism in perfused rat livers. I. Protein synthesis and entry into the plasma. J. din. Invest. 41, 842—849 (1962). 

Albumin (69 kDa) is the major protein of human plasma (3.4-4.7 g/dL) and makes up approximately 60% of the total plasma protein. About 40% of albumin is present in the plasma, and the other 60% is present in the extracellular space. The liver produces about 12 g of albumin per day, representing about 25% of total hepatic protein synthesis and half its secreted protein. Albumin is initially synthesized as a preproprotein. Its signal peptide is removed as it passes into the cisternae of the rough endoplasmic reticulum, and a hexapeptide at the resulting amino terminal is subsequently cleaved off farther along the secretory pathway. The synthesis of albumin is depressed in a variety of diseases, particularly those of the liver. The plasma of patients with liver disease often shows a decrease in the ratio of albumin to globulins (decreased albumin-globuhn ratio). The synthesis of albumin decreases rela-... 

A decrease in the concentration of plasma proteins causes a decrease in the plasma colloid osmotic pressure. As a result, filtration is increased, reabsorption is decreased, and fluid accumulates in the tissue. Most plasma proteins are made in the liver therefore, a decrease in protein synthesis due to liver failure is an important cause of this condition. Malnutrition may also impair protein synthesis. Finally, kidney disease leading to proteinuria (protein loss in the urine) decreases the concentration of plasma proteins. 

Synthesis and degradation. Most plasma proteins are synthesized by the liver. Exceptions to this include the immunoglobulins, which are secreted by B lymphocytes known... 

Zidovudine was the first drug of the class. It is a dideoxythymidine analog. It has to be phos-phorylated to the active triphosphate. This triphosphate is a competitive inhibitor of HIV reverse transcriptase. By incorporation into viral DNA it also acts as a chain-terminator of DNA synthesis. Mutations in viral reverse transcriptase are responsible for rapidly occurring resistance. Zidovudine slows disease progression and the occurrence of complications in AIDS patients. It is readily absorbed. However, first pass metabolism reduces its oral bioavailability with some 40%. It readily crosses the blood-brain barrier. Plasma protein binding is about 30%. Zidovudine is glucuronidated in the liver to an inactive metabolite. Its elimination half-life is 1 hour. 

Mechanism of Action Aketolide that blocks protein synthesis by binding to ribosomal receptor sites on the bacterial cell wall. Therapeutic Effect Bactericidal. Pharmacokinetics Protein binding 60%-70%. More of drug is concentrated in WBCs than in plasma, and drug is eliminated more slowly fromWBCs than from plasma. Partially metabolized by the liver. Minimally excreted in feces and urine. Half-life 10 hr. 

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. 

Protein degradation and amino acid metabolism are highly elevated in the diabetic, because the stimulatory effect of insulin on protein synthesis is nonexistent and the relative excess of glucagon and glucocorticoids causes protein breakdown to continue. Indeed, muscle wasting is a cardinal symptom of the untreated diabetic. Insulin also inhibits amino add release into the bloodstream, and this may be a reason a moderate rise in plasma amino add levels is observed in the diabetic. Such increased amino adds are largely of the branched-chain type, and alanine levels are in fact lower than normal. Nevertheless, alanine uptake by the liver is twice that of the normal individual, and it continues to be a major actor in the gluconeogenesis process. 

Increased portal blood pressure Blood flow in the portal system is often obstructed in cirrhosis, resulting in an increased portal blood pressure. Further, colloidal osmotic pressure of the blood is decreased as a result of impaired synthesis of plasma proteins by the diseased liver. Increased portal blood pressure and low osmo-larity of the blood cause fluid to escape from the portal vascular system and collect in the abdomen. 

Pharmacokinetics Itraconazole is well-absorbed orally and food increases its bioavailability. It is extensively bound to plasma proteins and distributes well throughout most tissues, including bone, sputum and adipose tissues. However, therapeutic concentrations are not attained in the CSF. Like ketoconazole it is extensively metabolized in the liver but does not inhibit androgen synthesis. Little of the parent drug appears in the urine and thus doses do not have to be reduced in renal failure. 

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