Akeno N, Saikatsu S, Kimura S, Horiuchi N
Department of Biochemistry, Ohu University School of Dentistry, Koriyama, Japan.
Biochem Pharmacol. 1994 Nov 29;48(11):2081-90. doi: 10.1016/0006-2952(94)90508-8.
The synthetic analog of 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], 22-oxacalcitriol (OCT), retains most of the properties of 1,25(OH)2D3 but exhibits much less hypercalcemic action than the parent compound. The effects of OCT on plasma calcium, phosphorus, and 1 alpha,25-dihydroxyvitamin D [1,25(OH)2D] concentrations were examined in mice. Administration of a single dose (24 pmol/g body wt, i.p.) of OCT had no effect on plasma calcium for up to 48 hr, significantly increased plasma phosphorus at 4 and 8 hr and significantly reduced the concentration of 1,25(OH)2D in plasma between 4 and 48 hr. Both OCT and 1,25(OH)2D3 at 24 pmol/g body wt (i.p.) induced a single, 3.4-kb mRNA encoding vitamin D 24-hydroxylase (24-OHase), the cytochrome P450 enzyme responsible for 1,25(OH)2D3 degradation, in kidney and duodenum. The OCT-induced increase in 24-OHase mRNA and an increase in enzyme activity were marked at 2 and 4 hr in both tissues. In kidney, mRNA abundance had decreased by 8 hr but remained above basal values for up to 30 hr; activity remained relatively high for up to 48 hr. In duodenum, 24-OHase mRNA abundance returned virtually to control values by 8 hr after OCT treatment; activity remained at nearly maximal levels for up to 30 hr but was decreased at 48 hr. The effects of OCT and 1,25(OH)2D3 on 24-OHase mRNA abundance and enzyme activity were dose-dependent in kidney and duodenum. Whereas the dose-response relations for the effects of both compounds on 24-OHase mRNA were similar, OCT was slightly more potent than 1,25(OH)2D3 in stimulating 24-OHase activity in both tissues. These results suggest that the OCT-induced decrease in plasma 1,25(OH)2D3 is attributable, at least in part, to an increased degradation of 1,25(OH)2D3, which results from an increase in 24-OHase abundance and enzyme activity.
1α,25 - 二羟基维生素D3[1,25(OH)2D3]的合成类似物22 - 氧杂骨化三醇（OCT）保留了1,25(OH)2D3的大部分特性，但与母体化合物相比，其高钙血症作用要小得多。研究了OCT对小鼠血浆钙、磷以及1α,25 - 二羟基维生素D[1,25(OH)2D]浓度的影响。腹腔注射单剂量（24 pmol/g体重）的OCT在长达48小时内对血浆钙无影响，在4小时和8小时时显著增加血浆磷，并在4至48小时之间显著降低血浆中1,25(OH)2D的浓度。腹腔注射24 pmol/g体重的OCT和1,25(OH)2D3均在肾脏和十二指肠中诱导出一种编码维生素D 24 - 羟化酶（24 - OHase）的3.4 kb mRNA，该细胞色素P450酶负责1,25(OH)2D3的降解。在两个组织中，OCT诱导的24 - OHase mRNA增加和酶活性增加在2小时和4小时时很明显。在肾脏中，mRNA丰度在8小时时下降，但在长达30小时内仍高于基础值；活性在长达48小时内保持相对较高。在十二指肠中，OCT处理后8小时，24 - OHase mRNA丰度几乎恢复到对照值；活性在长达30小时内保持在几乎最高水平，但在48小时时下降。OCT和1,25(OH)2D3对肾脏和十二指肠中24 - OHase mRNA丰度和酶活性的影响呈剂量依赖性。虽然两种化合物对24 - OHase mRNA影响的剂量 - 反应关系相似，但在刺激两个组织中的24 - OHase活性方面，OCT比1,25(OH)2D3稍强。这些结果表明，OCT诱导的血浆1,25(OH)2D3降低至少部分归因于1,25(OH)2D3降解增加，这是由24 - OHase丰度和酶活性增加所致。
