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Received for publication June 10, 2005.
Revised October 17, 2005.
Accepted for publication October 19, 2005.
The mechanisms underlying interindividual variation and developmental changes in CYP3A expression and activity are not fully understood. Quantitative RT-PCR methods were used to detect, during human fetal and pediatric development, mRNA expression of nuclear receptors involved in the regulation of CYP3A genes. Quantitative RT-PCR was conducted on RNA extracted from prenatal (n=60, 76 d to 32 wks EGA) and pediatric (n=20, 4 d to 18 yrs of age) liver tissue with primers for nuclear receptors implicated in regulating CYP3A gene expression. PXR and CAR were expressed at low (and highly variable) levels in pre- and neonatal liver relative to liver tissue derived from older children. CAR was expressed at higher levels relative to PXR in prenatal liver (757 ± 480 molecules CAR/ng RNA vs. 271 ± 190 molecules PXR/ng RNA after correction for 18S rRNA). In contrast, mRNA expression of the heterodimer partner, RXR
, was less variable (33-fold) and did not differ appreciably between pre- and postnatal liver samples (219 ± 101 molecules/ng RNA prenatal versus 253 ± 232 molecules/ng RNA postnatal). Expression of HNF41 mRNA was similar to that of RXR. LogCYP3A7 mRNA expression was significantly correlated with PXR (r2=0.372) and CAR (r2=0.380) mRNA in fetal liver but associations were weaker than those observed with CYP3A4 mRNA in postnatal liver (r2=0.610 and 0.723 for PXR and CAR, respectively). In conclusion, nuclear receptor mRNA expression demonstrates considerable interindividual variability in human fetal and pediatric liver and is significantly correlated with CYP3A expression.
Key words:
CAR, CYP3A, developmental pharmacology, gene regulation, nuclear receptors, PXR, regulation of gene expression, RXR
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