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Expression of CYP 3A4 and CYP 3A7 in Human Foetal Tissues and its Correlation with Nuclear Receptors
Author(s) -
Betts Stina,
BjörkhemBergman Linda,
Rane Anders,
Ekström Lena
Publication year - 2015
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12392
Subject(s) - pregnane x receptor , constitutive androstane receptor , nuclear receptor , calcitriol receptor , receptor , cytochrome p450 , biology , cyp3a4 , gene expression , medicine , taqi , endocrinology , peroxisome proliferator activated receptor , gene , biochemistry , allele , metabolism , polymorphism (computer science) , transcription factor
Previous reports have suggested that the nuclear receptors vitamin D receptor ( VDR ), peroxisome proliferator‐activated receptor α ( PPAR α), pregnane X receptor ( PXR ) and constitutive androstane receptor ( CAR ) are involved in the regulation of the drug‐metabolizing enzyme cytochrome P450 ( CYP ) 3A4 expression in adults. The aim of this study was to investigate the gene expression of CYP 3A4 and the foetal CYP 3A7 in human foetal tissues and their relation to gene expression and genetic variations in the nuclear receptors VDR , PPAR α, PXR and CAR . We determined the relative expression of CYP 3A4 and CYP 3A7 and these nuclear receptors in foetal livers, intestines and adrenals, using quantitative PCR . In addition, the expression of these enzymes was also analysed in adult liver. There was a high interindividual variability in CYP 3A4 and CYP 3A7, 49 times and 326 times, respectively. Both CYP 3A4 and CYP 3A7 had the highest expression in the liver. There were significant correlations ( p < 0.001) between the nuclear receptors studied and the expression of CYP 3A4 and CYP 3A7 in foetal liver, as well as the expression of CYP 3A4 in foetal intestine. Polymorphisms in the VDR gene, rs1544410 and rs1523130 ( TaqI ), in the PXR gene, rs1523130, and in the PPAR α gene, rs4253728, were not correlated with CYP 3A4 or CYP 3A7 expression. However, C‐homozygous individuals of the TaqI VDR polymorphism had 60% lower VDR gene expression ( p < 0.05), than individuals carrying one or two T alleles. In conclusion, differences in the expression of nuclear receptors might determine the variability in CYP 3A4 and CYP 3A7 expression observed in foetal liver.