Tiosano D, Weisman Y, Hochberg Z
Department of Pediatrics, Rambam Medical Center, Haifa 31096, Israel.
J Clin Endocrinol Metab. 2001 May;86(5):1908-12. doi: 10.1210/jcem.86.5.7448.
In vitro studies and animal experiments suggest that the production of 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] and 24,25-(OH)(2)D is reciprocally controlled by 1,25-(OH)(2)D. To investigate the role of the vitamin D receptor (VDR) in controlling vitamin D metabolism in humans, we studied 10 patients with vitamin D-dependent rickets type II due to a defective VDR. After a period of high dose calcium therapy, 7 of the patients had normal serum calcium, phosphorus, alkaline phosphatase, and plasma PTH levels (PTH-N), and 3 showed increased serum alkaline phosphatase and plasma PTH (PTH-H). Serum calcium, phosphorus, alkaline phosphatase, PTH, vitamin D metabolites, urinary calcium/creatinine, and renal phosphate threshold concentration were compared with unaffected family members that comprised the control group. Vitamin D metabolites were measured before and after an oral load of 50,000 U/m(2) cholecalciferol. Compared with the control group, 1,25-(OH)(2)D levels were significantly higher and 24,25-(OH)(2)D levels were lower in the PTH-N group and even more so in the PTH-H group. 1alpha-Hydroxylase (1-OHase) and 24-OHase activities were estimated by the product/substrate ratio. In the PTH-N group, 1-OHase activity was higher and 24-OHase activity was lower than in controls. In the PTH-H group, 1-OHase activity was even higher, probably due to an additive effect of PTH. Thus, 1,25-(OH)(2)D-liganded VDR is a major control mechanism for vitamin D metabolism, and PTH exerts an additive effect. Assessment of the influence of 1,25-(OH)(2)D shows reciprocal control of enzyme activity in man, suppressing 1-OHase and stimulating 24-OHase activity.
体外研究和动物实验表明，1,25 - 二羟基维生素D [1,25-(OH)(2)D] 和24,25-(OH)(2)D的生成受1,25-(OH)(2)D的反向调控。为了研究维生素D受体（VDR）在调控人体维生素D代谢中的作用，我们对10例因VDR缺陷导致的II型维生素D依赖性佝偻病患者进行了研究。经过一段时间的高剂量钙治疗后，7例患者的血清钙、磷、碱性磷酸酶和血浆甲状旁腺激素水平正常（PTH - N），3例患者的血清碱性磷酸酶和血浆甲状旁腺激素升高（PTH - H）。将血清钙、磷、碱性磷酸酶、甲状旁腺激素、维生素D代谢产物、尿钙/肌酐以及肾磷酸盐阈值浓度与作为对照组的未受影响的家庭成员进行比较。在口服50,000 U/m(2)胆钙化醇负荷前后测量维生素D代谢产物。与对照组相比，PTH - N组的1,25-(OH)(2)D水平显著升高，24,25-(OH)(2)D水平降低，PTH - H组更是如此。通过产物/底物比值估算1α - 羟化酶（1 - OHase）和24 - 羟化酶（24 - OHase）活性。在PTH - N组中，1 - OHase活性高于对照组，24 - OHase活性低于对照组。在PTH - H组中，1 - OHase活性甚至更高，可能是由于甲状旁腺激素的叠加作用。因此，1,25-(OH)(2)D结合的VDR是维生素D代谢的主要调控机制，甲状旁腺激素发挥叠加作用。对1,25-(OH)(2)D影响的评估显示，在人体中酶活性存在反向调控，抑制1 - OHase并刺激24 - OHase活性。
