1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10.
1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10.
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DOI：
10.1016/j.trsl.2016.07.006
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发表时间：
2016-12
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通讯作者：
Xiaoliang Wang;Hongwei Wang;B. Shen;B. Overholser;B. Cooper;Ying-fie Lu;Hua-mei Tang;Chongzhi Zhou;Xing Sun;L. Zhong;M. Favus;B. Decker;Wanqing Liu;Zhihai Peng
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作者：
Xiaoliang Wang;Hongwei Wang;B. Shen;B. Overholser;B. Cooper;Ying-fie Lu;Hua-mei Tang;Chongzhi Zhou;Xing Sun;L. Zhong;M. Favus;B. Decker;Wanqing Liu;Zhihai Peng
霉酚酸（MPA）是一种重要的免疫抑制剂，广泛应用于肾移植。然而，麦考酚酸（MPA）药代动力学（PK）的患者间差异较大，限制了其使用。我们推测MPA的肝外代谢可能对MPA的PK变异性有显著影响。两种肠道UDP-葡萄糖醛酸转移酶1A 8和1A 10在MPA代谢中发挥关键作用。计算机模拟和先前的全基因组分析都表明维生素D（VD）可能调节人UGT 1A的表达。我们通过染色质免疫沉淀（ChIP）和荧光素酶报告基因检测验证了UGT 1A基因座上的VD反应元件（VDRE）。在人肠细胞系LS 180、Caco-2和HCT-116中检测了1-α，25-二羟基维生素D3（D3）对UGT 1A 8和UGT 1A 10转录以及MPA葡萄糖醛酸化的影响。在人正常结直肠组织样本（n = 73）中检测VD受体（VDR）和两个UGT基因的转录水平之间的相关性。在肾移植受者（n = 10）中评估了母体药物霉酚酸酯（MMF）和D3治疗后MPA的PK变化。我们的ChIP测定验证了三个VDRE，其进一步被证明是荧光素酶测定的转录增强子。D3处理显著增加了细胞中UGT基因的转录以及MPA葡萄糖醛酸化。结直肠组织中VDRmRNA的表达与UGT 1A 8和UGT 1A 10的表达高度相关。D3治疗后MPA的AUC 0 - 12和Cmax均下降约40%，总清除率升高70%以上。提示VD通过调节肝外UGT活性对MPA代谢和PK具有重要的调节作用。
Mycophenolic acid (MPA) is an important immunosuppressant broadly used in renal transplantation. However, the large inter-patient variability in mycophenolic acid (MPA) pharmacokinetics (PK) limits its use. We hypothesize that extrahepatic metabolism of MPA may have significant impact on MPA PK variability. Two intestinal UDP-glucuronosyltransferases 1A8 and 1A10 plays critical role in MPA metabolism. Bothin silicoand previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinalUGT1Aexpression. We validated the VD response elements (VDREs) across theUGT1Alocus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) onUGT1A8andUGT1A10transcription and on MPA glucuronidation was tested in human intestinal cell lines LS180, Caco-2 and HCT-116. The correlation between transcription levels of VD receptor (VDR) and the two UGT genes were examined in human normal colorectal tissue samples (n = 73). PK alterations of MPA following the parent drug, mycophenolate mofetil (MMF), and D3 treatment was assessed among renal transplant recipients (n = 10). Our ChIP assay validate three VDREs which were further demonstrated as transcriptional enhancers with the luciferase assays. D3 treatment significantly increased transcription of both UGT genes as well as MPA glucuronidation in cells. TheVDRmRNA level was highly correlated with that of bothUGT1A8andUGT1A10in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12and Cmax while over 70% elevation of total clearance of MPA. Our study suggested a significant regulatory role of VD on MPA metabolism and PK via modulating extrahepatic UGT activity.