The Binding Properties, with Blood Proteins, and Tissue Distribution of 22-Oxa-1α, 25-Dihydroxyvitamin D3, a Noncalcemic Analogue of 1α, 25-Dihydroxyvitamin D3, in Rats1

Abstract

The binding properties, with blood proteins, and tissue distribution of 22-oxa-1 alpha,25-dihydroxyvitamin (22-oxacalcitriol; OCT), a noncalcemic analogue of 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], in rats were investigated. The binding affinity of OCT to plasma vitamin D binding protein (DBP) is extremely low and OCT mainly circulates in the blood as an intact form nonspecifically bound to lipoproteins especially to chylomicrons and low density lipoprotein (LDL). OCT intravenously injected into normal rats rats rapidly disappeared from the blood, and rapidly appeared in the bile as glucuronides of intact OCT and 1 alpha, 3 beta,20(S)-trihydroxy-9,10-secopregna-5,7,10(19)-triene (23,24,25,26, 27-pentanorOCT; pentanorOCT) as an OCT metabolite. When OCT or 1,25(OH)2D3 was injected into normal rats, significant amounts of OCT and 1,25(OH)2D3 were quickly detected in the thyroid and parathyroid glands, thymus, adrenals, liver, plasma, small intestine, kidneys, and calvaria. The detected amounts of OCT in the parathyroid glands, thymus, adrenals, liver, small intestine, and kidneys were significantly higher than the respective values for 1,25(OH)2D3 2 and/or 10 min after injection, while those of OCT in the plasma and calvaria were significantly lower than those of 1,25(OH)2D3. The in vivo rapid turn-over, nonspecific transportation, and incorporation of detectable amounts into the tissues are typical characteristics of OCT which may account for its specific activities.

In Vitro Metabolism of the Vitamin D Analog, 22-Oxacalcitriol, Using Cultured Osteosarcoma, Hepatoma, and Keratinocyte Cell Lines

“…Here we were able to augment the preliminary identification afforded by HPLC co-chromatography with GC-MS analysis and later comparison with chemically synthesized standards. Furthermore, our work is also consistent with the preliminary finding of a glucuronide conjugate of the 20-hydroxy compound in rat bile following OCT administration (10). The 24R-OH-OCT and 26-OH-OCT in the 25R-form identified here are novel, and their stereochemistry is also established.…”

“…Lastly, our finding of truncated versions of OCT would seem to open the door to study the origin of the conjugates found in bile in vivo following OCT administration to rats (10). The free 20-oxo or 20-hydroxy compounds identified here would likely be transported to the liver prior to conjugation to glucuronic acid in the hepatocyte, but this remains to be proven.…”

“…Because these cell models mimic vitamin D metabolism found in vivo, we expected to observe the same metabolites found and in some cases tentatively identified by others (10,11). In addition, our objective was to study the rate of OCT metabolism in various cell lines in order to gauge the involvement of vitamin D-inducible catabolic pathways as compared with more general metabolizing systems.…”

“…OCT binds poorly to the vitamin D binding protein (DBP) and is transported in the plasma bound by lipoproteins (chylomicrons and low density lipoprotein) in vivo (9), and this leads to an unusual distribution pattern with a degree of concentration of the vitamin D analog in parathyroid tissue (10). In contrast, little is known about OCT metabolism except that it appears to be excreted as a glucuronide conjugate in the bile, possibly a derivative of a truncated version of OCT (10).…”

“…In contrast, little is known about OCT metabolism except that it appears to be excreted as a glucuronide conjugate in the bile, possibly a derivative of a truncated version of OCT (10). Furthermore, there have been suggestions that a metabolite with a truncated side chain may be formed in bovine parathyroid cell cultures in vitro (11), although details of this have yet to be published.…”