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Transcriptional Regulators Predict CYP3A4 Expression in Human Pediatric Liver
Author(s) -
Vyhlidal Carrie A,
Bi Chengpeng,
Ye Shui Q,
Leeder J. Steven
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.713.1
Subject(s) - cyp3a4 , biology , gene expression , regulation of gene expression , messenger rna , gene , genetics , endocrinology , cytochrome p450 , metabolism
Members of the human CYP3A family of metabolizing enzymes exhibit extensive variability in catalytic activity. Up to 90% of the variation in CYP3A4 activity has been attributed to genetic factors; however, polymorphisms within the CYP3A4 gene do not adequately explain the observed variability. In pediatric liver, developmental changes in CYP3A4 expression are an additional source of variability. Recent studies have explored genetic and epigenetic variation and variable expression of regulatory factors as predictors of CYP3A4 activity. The objective of this study was to investigate the interactions between known regulatory factors of CYP3A4 and its expression in postnatal liver. The expression of genes encoding factors responsible for transcriptional regulation of CYP3A4 and modulators of CYP3A4 activity was determined by RNA‐Seq in 52 human postnatal liver samples (ages <1 day to 17 years of age). Individually, relative expression of total CYP3A4 mRNA in pediatric liver was significantly correlated (p<0.05 after Bonferroni correction) with the expression of PXR (r 2 =0.6), CAR (r 2 =0.59), LXRα (r 2 =0.46), ACSM3 (r 2 =0.69), AKR1D1 (r 2 =0.75), EHHADH (r 2 =0.67), FMO3 (r 2 =0.7), GLYAT (r 2 =0.64), and SLC10A1 (r 2 =0.68). Stepwise regression using minimum Bayesian Information Criterion was performed. The expression of CYP3A4 mRNA could be explained by a subset factors including CEBPA, FOXA3 (HNF3γ), RXRα, NFIA, AKR1D1, and FMO3 (r 2 =0.78, p=1.07*10 −12 ). In conclusion, these results suggest that transcriptional regulators of CYP3A4 are important contributing factors to variability in its mRNA expression in pediatric liver.