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Am J Physiol Gastrointest Liver Physiol 274: G1018-G1023, 1998;
0193-1857/98 $5.00
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Vol. 274, Issue 6, G1018-G1023, June 1998

Discrete roles of hepatocytes and nonparenchymal cells in uridine catabolism as a component of its homeostasis

M. P. Liu1, L. Beigelman2, E. Levy3, R. E. Handschumacher1, and G. Pizzorno1

1 Section of Medical Oncology, Departments of Internal Medicine and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520; 2 United States Biochemical, Cleveland, Ohio 44128; and 3 Abbott Diagnostics, Abbott Park, Illinois 60064

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 beta -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 µM) 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.

pyrimidines; metabolism; compartmentalization


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