1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10

Xiaoliang Wang, Hongwei Wang, Bing Shen, Brian R. Overholser, Bruce R. Cooper, Yinghao Lu, Huamei Tang, Chongzhi Zhou, Xing Sun, Lin Zhong, Murray J. Favus, Brian Decker, Wanqing Liu, Zhihai Peng

Research output: Contribution to journalArticle

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Abstract

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. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription 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. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12 and 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.

Original languageEnglish (US)
Pages (from-to)54-62.e6
JournalTranslational Research
Volume178
DOIs
StatePublished - Dec 1 2016

Fingerprint

Mycophenolic Acid
Glucuronosyltransferase
Transplants
Pharmacokinetics
Calcitriol
Kidney
Transcription
Metabolism
Assays
Genes
Chromatin Immunoprecipitation
Luciferases
Vitamin D
Chromatin
Vitamin D Response Element
Transplant Recipients
Tissue
Calcitriol Receptors
Response Elements
Immunosuppressive Agents

ASJC Scopus subject areas

  • Medicine(all)
  • Public Health, Environmental and Occupational Health
  • Biochemistry, medical

Cite this

1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10. / Wang, Xiaoliang; Wang, Hongwei; Shen, Bing; Overholser, Brian R.; Cooper, Bruce R.; Lu, Yinghao; Tang, Huamei; Zhou, Chongzhi; Sun, Xing; Zhong, Lin; Favus, Murray J.; Decker, Brian; Liu, Wanqing; Peng, Zhihai.

In: Translational Research, Vol. 178, 01.12.2016, p. 54-62.e6.

Research output: Contribution to journalArticle

Wang, Xiaoliang ; Wang, Hongwei ; Shen, Bing ; Overholser, Brian R. ; Cooper, Bruce R. ; Lu, Yinghao ; Tang, Huamei ; Zhou, Chongzhi ; Sun, Xing ; Zhong, Lin ; Favus, Murray J. ; Decker, Brian ; Liu, Wanqing ; Peng, Zhihai. / 1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10. In: Translational Research. 2016 ; Vol. 178. pp. 54-62.e6.
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abstract = "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. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription 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. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40{\%} reduction in both AUC0-12 and 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.",
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AU - Wang, Hongwei

AU - Shen, Bing

AU - Overholser, Brian R.

AU - Cooper, Bruce R.

AU - Lu, Yinghao

AU - Tang, Huamei

AU - Zhou, Chongzhi

AU - Sun, Xing

AU - Zhong, Lin

AU - Favus, Murray J.

AU - Decker, Brian

AU - Liu, Wanqing

AU - Peng, Zhihai

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