Abstract

1. Effects of cholecalciferol (VitD₃) and calcitriol (1,25-VitD₃), on the expression and function of major vitamin D metabolizing enzymes (cytochrome P450 [CYP]2R1, CYP24A1) and select drug transport pathways (ABCB1/P-gp, SLCO4C1/OATP4C1) were evaluated in human kidney proximal tubule epithelial cells (hPTECs) under normal and uraemic serum conditions.

2. hPTECs were incubated with 10% normal or uraemic serum for 24 h followed by treatment with 2% ethanol vehicle, or 100 and 240 nM doses of VitD₃, or 1,25-VitD₃ for 6 days. The effects of treatment on mRNA and protein expression and functional activity of select CYP enzymes and transporters were assessed

3. Under uraemic serum, treatment with 1,25-VitD₃ resulted in increased mRNA but decreased protein expression of CYP2R1. Activity of CYP2R1 was not influenced by serum or VitD analogues. CYP24A1 expression was increased with 1,25-VitD₃ under normal as well as uraemic serum, although to a lesser extent. ABCB1/P-gp mRNA expression increased under normal and uraemic serum, with exposure to 1,25-VitD₃. SLCO4C1/OATP4C1 exhibited increased mRNA but decreased protein expression, under uraemic serum + 1,25-VitD₃. Functional assessments of transport showed no changes regardless of exposure to serum or 1,25-VitD₃.

4. Key findings indicate that uraemic serum and VitD treatment led to differential effects on the functional expression of CYPs and transporters in hPTECs.

摘要

1. 胆钙化醇 (VitD ₃ ) 和骨化三醇 (1,25-VitD ₃ ) 对主要维生素 D 代谢酶（细胞色素 P450 [CYP]2R1、CYP24A1）的表达和功能以及选择药物转运途径（ABCB1/ P-gp）的影响, SLCO4C1 /OATP4C1) 在正常和尿毒症血清条件下在人肾近端小管上皮细胞 (hPTEC) 中进行评估。

2. hPTECs 与 10% 正常或尿毒症血清孵育 24 小时，然后用 2% 乙醇载体，或 100 和 240 nM 剂量的 VitD ₃或 1,25-VitD ₃处理 6 天。评估了治疗对选定 CYP 酶和转运蛋白的 mRNA 和蛋白质表达以及功能活性的影响

3. 在尿毒症血清下，用 1,25-VitD _{3 处理}导致 mRNA 增加，但 CYP2R1 的蛋白表达降低。CYP2R1 的活性不受血清或 VitD 类似物的影响。CYP24A1表达随 1,25-VitD ₃在正常和尿毒症血清下增加，但程度较轻。ABCB1 /P-gp mRNA 表达在正常和尿毒症血清下增加，暴露于 1,25-VitD ₃。在尿毒症血清 + 1,25-VitD ₃下，SLCO4C1 /OATP4C1 表现出增加的 mRNA 但降低蛋白质表达。无论是否接触血清或 1,25-VitD ₃，运输的功能评估均未显示任何变化。

4. 主要发现表明，尿毒症血清和 VitD 治疗对 hPTEC 中 CYP 和转运蛋白的功能表达产生了不同的影响。