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Metabolism of different molecular forms of adenosine deaminase intravenously infused into the rabbit
Abstract:
High-Mr and monomeric adenosine deaminase were injected intravenously into the rabbit. The rates of clearance and sites of uptake of the enzymes were compared. Calf intestinal mucosa served as the source of monomeric adenosine deaminase. High-Mr enzymes were assembled in vitro from the calf enzyme and adenosine deaminase-complexing proteins isolated from rabbit plasma or kidney. An immunoassay specific for calf adenosine deaminase was used to determine which organs took up the injected enzyme. The enzymes were cleared from circulation in the following order: monomeric adenosine deaminase greater than high-Mr enzyme prepared with kidney complexing protein greater than high-Mr enzyme prepared with plasma complexing protein. High-Mr enzyme assembled with kidney complexing protein was taken up primarily by the liver. Complexing protein and adenosine deaminating activity were cleared from circulation at similar rates. This and other evidence indicate that kidney complexing protein and calf adenosine deaminase are taken up as a unit by the liver. In contrast, adenosine-deaminating activity was cleared more quickly from circulation than complexing protein in rabbits injected with enzyme prepared with plasma complexing protein. Immunoassay results indicated that calf adenosine deaminase was taken up principally by the kidney cortex and liver. Kidney was the major site of uptake of monomeric adenosine deaminase. Indirect immunoperoxidase staining was used to localize the calf enzyme in glomeruli and proximal renal tubules, the same areas in which rabbit complexing protein is localized. These results support the hypothesis that complexing proteins play a role in the clearance of adenosine deaminase from plasma [W.P. Schrader and P.J. Bryer (1982) Arch. Biochem. Biophys. 215, 107-115].
Insights
High molecular weight (High-Mr) adenosine deaminase, when complexed with kidney proteins, is cleared by the liver. Monomeric adenosine deaminase is primarily cleared by the kidney.
Area of Science:
- Biochemistry
- Pharmacokinetics
- Enzymology
Background:
- Adenosine deaminase (ADA) is a critical enzyme in purine metabolism.
- Understanding the clearance mechanisms of ADA is essential for its therapeutic applications.
- The role of complexing proteins in enzyme clearance is not fully elucidated.
Purpose of the Study:
- To compare the clearance rates and tissue uptake of monomeric and high molecular weight (High-Mr) adenosine deaminase (ADA) in rabbits.
- To investigate the influence of adenosine deaminase-complexing proteins from kidney and plasma on enzyme disposition.
- To determine the specific organs responsible for the uptake of different forms of ADA.
Main Methods:
- Intravenous injection of monomeric and High-Mr ADA (assembled in vitro) into rabbits.
- Quantification of enzyme clearance rates from circulation.
- Organ-specific uptake determination using a specific immunoassay for calf ADA and indirect immunoperoxidase staining.
Main Results:
- Clearance order: monomeric ADA > High-Mr ADA (kidney complex) > High-Mr ADA (plasma complex).
- High-Mr ADA with kidney complexing protein was primarily taken up by the liver, suggesting unit uptake.
- Monomeric ADA and High-Mr ADA with plasma complexing protein were mainly taken up by the kidney cortex and liver, with kidney being the major site for monomeric ADA.
Conclusions:
- Complexing proteins significantly influence the clearance and tissue distribution of adenosine deaminase.
- Kidney complexing protein facilitates hepatic uptake of ADA as a complex.
- These findings support the hypothesis that complexing proteins play a crucial role in plasma ADA clearance.