Inosine metabolism in the rat

Area of Science:

• Biochemistry
• Metabolic pathways
• Nucleoside metabolism

Background:

• Inosine is a vital nucleoside involved in purine metabolism.
• Understanding inosine's distribution and metabolic fate is crucial for comprehending cellular energy homeostasis and salvage pathways.

Purpose of the Study:

• To investigate the in vivo uptake, distribution, and metabolism of inosine.
• To track the fate of purine and ribose components of inosine in various tissues.
• To elucidate the role of different organs in inosine processing and the subsequent disposition of its metabolites.

Main Methods:

• Intravenous administration of doubly labeled inosine in a preclinical model.
• Quantification of radioactivity in plasma and key organs (liver, kidney, heart, lung, skeletal muscle) over time.
• Analysis of differential incorporation and loss of purine and ribose moieties in various tissues.

Main Results:

• Inosine was rapidly cleared from plasma (>99% within 20 min).
• Kidneys showed the highest initial uptake, followed by the liver, while lung and heart had minimal incorporation.
• Skeletal muscle demonstrated a significant increase in radioactivity over 60 minutes, accumulating 40% of the injected dose.
• Differential metabolism was observed: kidneys lost inosine, hearts lost purines, lungs lost ribose, and liver retained purines while losing ribose.
• A portion of ribose was converted to glucose, increasing blood glucose levels and stimulating insulin release.
• Radioactive purines and ribose (as glucose) accumulated in skeletal muscle.

Conclusions:

• Inosine is rapidly cleared and distributed, with significant initial uptake by metabolically active organs like the kidney and liver.
• Skeletal muscle serves as a major long-term reservoir for inosine-derived purine and ribose metabolites.
• The observed conversion of ribose to glucose and subsequent hyperglycemia highlights a potential role for inosine in glucose homeostasis.