Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada, M5S 3 M2.
Biopharm Drug Dispos. 2013 Oct;34(7):402-16. doi: 10.1002/bdd.1856. Epub 2013 Sep 16.
Previous studies have shown that 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ] treatment in mice resulted in induction of intestinal and renal Cyp24a1 and Trpv6 expression, increased hepatic Cyp7a1 expression and activity, as well as higher renal Mdr1/P-gp expression. The present study compared the equimolar efficacies of 1α-hydroxyvitamin D3 [1α(OH)D3 ] (6 nmol/kg i.p. q2d × 4), a lipophilic precursor with a longer plasma half-life that is converted to 1,25(OH)2 D3 , and 1,25(OH)2 D3 on vitamin D receptor (VDR) target genes. To clarify whether changes in VDR genes was due to VDR and not secondary, farnesoid X receptor (FXR)-directed effects, namely, lower Cyp7a1 expression in rat liver due to increased bile acid absorption, wildtype [fxr(+/+)] and FXR knockout [fxr(-/-)] mice were used to distinguish between VDR and FXR effects. With the exception that hepatic Sult2a1 mRNA was increased equally well by 1α(OH)D3 and 1,25(OH)2 D3 , 1α(OH)D3 treatment led to higher increases in hepatic Cyp7a1, renal Cyp24a1, VDR, Mdr1 and Mrp4, and intestinal Cyp24a1 and Trpv6 mRNA expression in both fxr(+/+) and fxr(-/-) mice compared to 1,25(OH)2 D3 treatment. A similar induction in protein expression and microsomal activity of hepatic Cyp7a1 and renal P-gp and Mrp4 protein expression was noted for both compounds. A higher intestinal induction of Trpv6 was observed, resulting in greater hypercalcemic effect following 1α(OH)D3 treatment. The higher activity of 1α(OH)D3 was explained by its rapid conversion to 1,25(OH)2 D3 in tissue sites, furnishing higher plasma and tissue 1,25(OH)2 D3 levels compared to following 1,25(OH)2 D3 -treatment. In conclusion, 1α(OH)D3 exerts a greater effect on VDR gene induction than equimolar doses of 1,25(OH)2 D3 in mice.
先前的研究表明，1α，25-二羟维生素 D3（1，25（OH）2 D3）治疗可诱导小鼠肠道和肾脏 Cyp24a1 和 TRPV6 的表达，增加肝脏 Cyp7a1 的表达和活性，并增加肾脏 Mdr1/P-gp 的表达。本研究比较了脂溶性前体 1α-羟维生素 D3（1α（OH）D3）（6 nmol/kg ip q2d×4）和 1，25（OH）2 D3 在维生素 D 受体（VDR）靶基因上的等摩尔功效。为了阐明 VDR 基因的变化是否是由于 VDR 而不是继发性的法尼醇 X 受体（FXR）的直接作用，即由于胆汁酸吸收增加而导致大鼠肝脏 Cyp7a1 表达降低，使用野生型 [fxr（+/+）] 和 FXR 敲除 [fxr（-/-）] 小鼠来区分 VDR 和 FXR 效应。除了肝 Sult2a1 mRNA 的增加同样可以通过 1α（OH）D3 和 1，25（OH）2 D3 来实现，与 1，25（OH）2 D3 处理相比，1α（OH）D3 处理导致野生型 [fxr（+/+）] 和 FXR 敲除 [fxr（-/-）] 小鼠肝脏 Cyp7a1、肾脏 Cyp24a1、VDR、Mdr1 和 Mrp4 以及肠道 Cyp24a1 和 TRPV6 mRNA 表达的增加更高。两种化合物均观察到肝 Cyp7a1 和肾 P-gp 和 Mrp4 蛋白表达的蛋白表达和微粒体活性的类似诱导。观察到肠道中 TRPV6 的诱导更高，导致 1α（OH）D3 治疗后血钙升高的作用更大。1α（OH）D3 的更高活性可以通过其在组织部位快速转化为 1，25（OH）2 D3 来解释，与 1，25（OH）2 D3 治疗相比，其提供了更高的血浆和组织 1，25（OH）2 D3 水平。总之，1α（OH）D3 在小鼠中对 VDR 基因诱导的作用大于等摩尔剂量的 1，25（OH）2 D3。
