Relationship between mRNA expression levels of CYP3A4, CYP3A5 and SXR in peripheral mononuclear blood cells and aging in young kidney transplant recipients under tacrolimus treatment

Mariano Ferraresso, Stefano Turolo, Mirco Belingheri, Amedea Silvia Tirelli, Ivan Cortinovis, Silvano Milani, Alberto Edefonti, Luciana Ghio

Research output: Contribution to journalArticle

Abstract

Aim: The activity of several key enzymes involved in the metabolism of many drugs is subject to change closely related to the age of patients. This possibility must also be considered in the case of tacrolimus, the most important calcineurins inhibitor, which is widely used in pediatric kidney transplantation. As well as in the liver and intestine, some of the enzymes involved in the metabolism of tacrolimus were also isolated in the peripheral blood mononuclear cells (PBMCs), where also appear to play an important regulatory action. Therefore, the influence of some external factors on the expression of specific mRNA can be determined noninvasively. Patients & methods: The correlation between the levels of mRNA specific for key enzymes SXR, CYP3A and ABCB1 involved in the metabolism of tacrolimus was evaluated in PBMCs obtained from a selected population of 29 young kidney transplant recipients. A possible correlation between the expression of these specific mRNAs and tacrolimus pharmacokinetics was also investigated. Results: The patients' age and their blood concentrations of SXR mRNA were directly correlated with the expression of CYP3A4, CYP3A5 mRNAs, but not of ABCB1 mRNA in the PBMCs. tacrolimus-normalized daily dose was strongly correlated with patient's age and multivariable regression indicates the CYP3A4-specific mRNA as the sole independent variable influencing tacrolimus concentration-to-dose ratio. Conclusion: Aging and SXR mRNA significantly affect the expression of CYP3A4- and CYP3A5-specific mRNA as measured by their concentration in PBMC.

Original languageEnglish
Pages (from-to)483-491
Number of pages9
JournalPharmacogenomics
Volume16
Issue number5
DOIs
Publication statusPublished - Apr 1 2015

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Cytochrome P-450 CYP3A
Cell Aging
Tacrolimus
Blood Cells
Kidney
Messenger RNA
Therapeutics
Enzymes
Transplant Recipients
Kidney Transplantation
Intestines
Pharmacokinetics
Pediatrics

Keywords

  • ABCB1
  • CYP3A4
  • CYP3A5
  • mRNA
  • Pediatric kidney transplant
  • Peripheral blood mononuclear cells
  • SXR
  • Tacrolimus

ASJC Scopus subject areas

  • Pharmacology
  • Genetics
  • Molecular Medicine
  • Medicine(all)

Cite this

@article{6cd5f984d4f04dd69d258a4a24502ec7,
title = "Relationship between mRNA expression levels of CYP3A4, CYP3A5 and SXR in peripheral mononuclear blood cells and aging in young kidney transplant recipients under tacrolimus treatment",
abstract = "Aim: The activity of several key enzymes involved in the metabolism of many drugs is subject to change closely related to the age of patients. This possibility must also be considered in the case of tacrolimus, the most important calcineurins inhibitor, which is widely used in pediatric kidney transplantation. As well as in the liver and intestine, some of the enzymes involved in the metabolism of tacrolimus were also isolated in the peripheral blood mononuclear cells (PBMCs), where also appear to play an important regulatory action. Therefore, the influence of some external factors on the expression of specific mRNA can be determined noninvasively. Patients & methods: The correlation between the levels of mRNA specific for key enzymes SXR, CYP3A and ABCB1 involved in the metabolism of tacrolimus was evaluated in PBMCs obtained from a selected population of 29 young kidney transplant recipients. A possible correlation between the expression of these specific mRNAs and tacrolimus pharmacokinetics was also investigated. Results: The patients' age and their blood concentrations of SXR mRNA were directly correlated with the expression of CYP3A4, CYP3A5 mRNAs, but not of ABCB1 mRNA in the PBMCs. tacrolimus-normalized daily dose was strongly correlated with patient's age and multivariable regression indicates the CYP3A4-specific mRNA as the sole independent variable influencing tacrolimus concentration-to-dose ratio. Conclusion: Aging and SXR mRNA significantly affect the expression of CYP3A4- and CYP3A5-specific mRNA as measured by their concentration in PBMC.",
keywords = "ABCB1, CYP3A4, CYP3A5, mRNA, Pediatric kidney transplant, Peripheral blood mononuclear cells, SXR, Tacrolimus",
author = "Mariano Ferraresso and Stefano Turolo and Mirco Belingheri and Tirelli, {Amedea Silvia} and Ivan Cortinovis and Silvano Milani and Alberto Edefonti and Luciana Ghio",
year = "2015",
month = "4",
day = "1",
doi = "10.2217/pgs.15.18",
language = "English",
volume = "16",
pages = "483--491",
journal = "Pharmacogenomics",
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T1 - Relationship between mRNA expression levels of CYP3A4, CYP3A5 and SXR in peripheral mononuclear blood cells and aging in young kidney transplant recipients under tacrolimus treatment

AU - Ferraresso, Mariano

AU - Turolo, Stefano

AU - Belingheri, Mirco

AU - Tirelli, Amedea Silvia

AU - Cortinovis, Ivan

AU - Milani, Silvano

AU - Edefonti, Alberto

AU - Ghio, Luciana

PY - 2015/4/1

Y1 - 2015/4/1

N2 - Aim: The activity of several key enzymes involved in the metabolism of many drugs is subject to change closely related to the age of patients. This possibility must also be considered in the case of tacrolimus, the most important calcineurins inhibitor, which is widely used in pediatric kidney transplantation. As well as in the liver and intestine, some of the enzymes involved in the metabolism of tacrolimus were also isolated in the peripheral blood mononuclear cells (PBMCs), where also appear to play an important regulatory action. Therefore, the influence of some external factors on the expression of specific mRNA can be determined noninvasively. Patients & methods: The correlation between the levels of mRNA specific for key enzymes SXR, CYP3A and ABCB1 involved in the metabolism of tacrolimus was evaluated in PBMCs obtained from a selected population of 29 young kidney transplant recipients. A possible correlation between the expression of these specific mRNAs and tacrolimus pharmacokinetics was also investigated. Results: The patients' age and their blood concentrations of SXR mRNA were directly correlated with the expression of CYP3A4, CYP3A5 mRNAs, but not of ABCB1 mRNA in the PBMCs. tacrolimus-normalized daily dose was strongly correlated with patient's age and multivariable regression indicates the CYP3A4-specific mRNA as the sole independent variable influencing tacrolimus concentration-to-dose ratio. Conclusion: Aging and SXR mRNA significantly affect the expression of CYP3A4- and CYP3A5-specific mRNA as measured by their concentration in PBMC.

AB - Aim: The activity of several key enzymes involved in the metabolism of many drugs is subject to change closely related to the age of patients. This possibility must also be considered in the case of tacrolimus, the most important calcineurins inhibitor, which is widely used in pediatric kidney transplantation. As well as in the liver and intestine, some of the enzymes involved in the metabolism of tacrolimus were also isolated in the peripheral blood mononuclear cells (PBMCs), where also appear to play an important regulatory action. Therefore, the influence of some external factors on the expression of specific mRNA can be determined noninvasively. Patients & methods: The correlation between the levels of mRNA specific for key enzymes SXR, CYP3A and ABCB1 involved in the metabolism of tacrolimus was evaluated in PBMCs obtained from a selected population of 29 young kidney transplant recipients. A possible correlation between the expression of these specific mRNAs and tacrolimus pharmacokinetics was also investigated. Results: The patients' age and their blood concentrations of SXR mRNA were directly correlated with the expression of CYP3A4, CYP3A5 mRNAs, but not of ABCB1 mRNA in the PBMCs. tacrolimus-normalized daily dose was strongly correlated with patient's age and multivariable regression indicates the CYP3A4-specific mRNA as the sole independent variable influencing tacrolimus concentration-to-dose ratio. Conclusion: Aging and SXR mRNA significantly affect the expression of CYP3A4- and CYP3A5-specific mRNA as measured by their concentration in PBMC.

KW - ABCB1

KW - CYP3A4

KW - CYP3A5

KW - mRNA

KW - Pediatric kidney transplant

KW - Peripheral blood mononuclear cells

KW - SXR

KW - Tacrolimus

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DO - 10.2217/pgs.15.18

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VL - 16

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JO - Pharmacogenomics

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SN - 1462-2416

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