Discrete roles of hepatocytes and nonparenchymal cells in uridine catabolism as a component of its homeostasis.
Previous studies indicated that uridine is essentially cleared in a single pass through a rat liver and replaced in a highly regulated manner by uridine formed presumably by de novo synthesis. We report a cellular basis for the catabolic component of this apparent paradox by dissociation of the liver with collagenase into two cell fractions, hepatocytes and a nonparenchymal cell population. Suspensions of the nonparenchymal cells rapidly cleave uridine to uracil, whereas in hepatocytes this activity was <5% of that in nonparenchymal cells. Conversely, hepatocytes cause extensive degradation of uracil to -alanine. These differences correlate with the uridine phosphorylase and dihydrouracil dehydrogenase activity in cell-free extracts of each cell type. We have documented the existence of a Na+-dependent, nitrobenzylthioinosine-insensitive transport system for uridine in the parenchymal cells (Michaelis constant 46 +/- 5 microM) that achieves a three- to fourfold concentration gradient in hepatocytes. A similar system is present in the nonparenchymal cell population. In addition, a highly specific and active Na+-dependent transport system for beta-alanine, the primary catabolic metabolite of uracil, has been demonstrated in hepatocytes.
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
M P
MP
Liu
L
L
Beigelman
E
E
Levy
R E
RE
Handschumacher
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G
Pizzorno
D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D050744:Dihydrouracil Dehydrogenase (NAD+); D006706:Homeostasis; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D010088:Oxidoreductases / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000494:pharmacology; D014498:Uracil / Q000378:metabolism; D014529:Uridine / Q000378:metabolism*; D014543:Uridine Phosphorylase / Q000378:metabolism; D015091:beta-Alanine / Q000378:metabolism
D015091:beta-Alanine; D014498:Uracil; D012964:Sodium; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050744:Dihydrouracil Dehydrogenase (NAD+); D014543:Uridine Phosphorylase; D014529:Uridine