Effects of purine derivatives on calcitriol metabolism in rats.
The effects of theophylline and sodium urate on metabolic production (PR) and clearance rate (MCR) of calcitriol were determined by the constant isotope infusion method in normal rats. Calcitriol PR was significantly reduced after infusion for 20 h of either theophylline (1 mg/h, PR = 22.3 +/- 1.6 ng.kg-1.day-1, P less than 0.001, n = 5) or sodium urate (0.5 mg/h, PR = 18.6 +/- 1.2 ng.kg-1.day-1, P less than 0.001, n = 5) compared with control rats infused with saline (PR = 32.0 +/- 1.5 ng.kg-1.day-1, n = 5). Renal 1 alpha-hydroxylase activity of kidney homogenate was significantly inhibited in rats infused with theophylline or urate. Suppression of 1 alpha-hydroxylase activity was also observed when the kidney homogenate was preincubated for 3 h with various concentrations of xanthine (0.11-3.0 mg/dl). In addition, the MCR of calcitriol was decreased in rats infused with either theophylline (MCR = 21.0 +/- 0.88 microliter.min-1.100 g-1, P less than 0.005) or urate (MCR = 22.9 +/- 0.91 microliter.min-1.100 g-1, P less than 0.05) compared with saline-infused control rats (MCR = 25.2 +/- 0.41 microliter.min-1.100 g-1). Because calcitriol degradation is a receptor-mediated process that requires binding of the receptor-hormone complex to chromatin, we studied the binding affinity of labeled calcitriol receptor for DNA-cellulose in the presence of theophylline or urate. Both theophylline and urate inhibited receptor binding affinity for DNA-cellulose. We conclude that these purine derivatives suppress calcitriol synthesis and inhibit receptor binding affinity for DNA. The altered receptor binding affinity could explain the decreased MCR of calcitriol.
Hsu
C H
CH
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109-0364.
Patel
S R
SR
Young
E W
EW
Vanholder
R
R
D000818:Animals; D002117:Calcitriol / Q000378:metabolism*; D002482:Cellulose / Q000031:analogs & derivatives / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase; D004247:DNA / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D013806:Theophylline / Q000494:pharmacology; D014527:Uric Acid / Q000494:pharmacology
C033190:DNA-cellulose; D011687:Purines; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D014527:Uric Acid; D002482:Cellulose; D004247:DNA; D013806:Theophylline; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase; D002117:Calcitriol