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.
OBJECTIVE
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.


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.


CONCLUSIONS
Aging and SXR mRNA significantly affect the expression of CYP3A4- and CYP3A5-specific mRNA as measured by their concentration in PBMC.
Department of Clinical Sciences & Community Health, University of Milan, Via F. Sforza 35, 20122 Milan, Italy.
Mariano
M
Ferraresso
Stefano
S
Turolo
Mirco
M
Belingheri
Amedea Silvia
AS
Tirelli
Ivan
I
Cortinovis
Silvano
S
Milani
Alberto
A
Edefonti
Luciana
L
Ghio
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D000293:Adolescent; D000375:Aging / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D009000:Monocytes / Q000201:enzymology*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000096:biosynthesis; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000235:genetics*; D016559:Tacrolimus / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D007166:Immunosuppressive Agents; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus
ABCB1; CYP3A4; CYP3A5; SXR; mRNA; pediatric kidney transplant; peripheral blood mononuclear cells; tacrolimus