Despite recent rapid progress in understanding the expression patterns and regulatory mechanisms of drug processing genes, namely drug metabolizing enzymes and transporters in adults, little is known about these in the pediatric period. The long-term goal is to understand mechanisms of ontogenic regulation of drug processing genes, so that efficacious and safe drug treatments can be achieved in children. Several factors are known to be essential for normal development, including hepatocyte nuclear factor 11 (HNF11), farnesoid X receptor (FXR), growth hormone (GH) signaling, and epigenetic influences. HNF11, a master regulator of early liver development, regulates hepatic expression of a large battery of drug processing genes. Initiation of bile-acid signaling pathways, mediated largely via the FXR, is a hallmark of perinatal liver development. GH is essential for postnatal hepatic gene expression and maturation. The accessibility of transcription factors to the target genes is largely determined by the methylation/acetylation status of histones and DNA sequences. Preliminary studies illustrate that in developing mouse livers, drug processing genes and transcription factors are expressed in distinct dynamic patterns and correlate with epigenetic signatures. The objective of this proposal is to elucidate the regulatory mechanisms of ontogenic expression of drug processing genes in mice. The rationale of this proposal is that its successful completion will generate basic knowledge that will serve as the foundation for further understanding pediatric pharmacology in humans. The central hypothesis is: developmental regulation of drug processing genes is a sequential event regulated by hormones, which activate transcription factors to modify epigenetic signatures and regulate gene expression. This hypothesis will be tested in 2 aims.
Aim 1 will determine the ontogenic expression patterns of drug processing genes and the correlation with transcription factors and epigenetic signatures. The relative mRNA expression of major phase I/II enzymes and drug transporters in male mouse livers versus intestine and kidney will be examined, and correlated with expression of transcription factors and chromosome modifications (genome-wide DNA methylation and histone modifications).
Aim 2 will elucidate roles of transcription factors and GH in determining ontogenic hepatic expression of drug processing genes in HNF11-null, FXR-null, and GH deficiency (lit/lit) mice using the same working strategy. This study is novel, because it will use a genome-wide approach to elucidate how alterations of hormones and transcription factors modulate epigenetic signatures and hepatic ontogenic expression of drug processing genes. This study is significant, because little is known about the regulation of hepatic drug processing genes in pediatric stages. Results from this study will: 1) provide basic knowledge on the ontogenic expression patterns of drug processing genes and nuclear receptors in liver, kidney, and intestine;and 2) help to understand how perinatal alterations in hormones and nuclear receptors, via modulating epigenetic signatures, affect stage-specific and long-term expression of drug processing genes.

Public Health Relevance

The proposed studies are of importance and an under-investigated area of regulatory mechanisms of the developmental expression patterns of genes important in the absorption, distribution, metabolism, and excretion of therapeutic drugs. Thus, the findings are expected to be applicable to the improvement of efficacy and safety of pediatric pharmacology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES019487-05
Application #
8663696
Study Section
Special Emphasis Panel (ZRG1-CB-L (50))
Program Officer
Tyson, Frederick L
Project Start
2010-05-03
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$568,007
Indirect Cost
$189,336
Name
University of Kansas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Li, Cindy Yanfei; Renaud, Helen J; Klaassen, Curtis D et al. (2016) Age-Specific Regulation of Drug-Processing Genes in Mouse Liver by Ligands of Xenobiotic-Sensing Transcription Factors. Drug Metab Dispos 44:1038-49
Dzierlenga, A L; Clarke, J D; Cherrington, N J (2016) Nonalcoholic Steatohepatitis Modulates Membrane Protein Retrieval and Insertion Processes. Drug Metab Dispos 44:1799-1807
Cui, Julia Yue; Klaassen, Curtis D (2016) RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome. Biochim Biophys Acta 1859:1198-217
Park, Shinhee; Cheng, Sunny Lihua; Cui, Julia Yue (2016) Characterizing drug-metabolizing enzymes and transporters that are bona fide CAR-target genes in mouse intestine. Acta Pharm Sin B 6:475-491
Tracy, Timothy S; Chaudhry, Amarjit S; Prasad, Bhagwat et al. (2016) Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism. Drug Metab Dispos 44:343-51
Guo, Ying; Zhang, YouCai; Huang, WeiHua et al. (2016) Dose-response effect of berberine on bile acid profile and gut microbiota in mice. BMC Complement Altern Med 16:394
Selwyn, Felcy Pavithra; Cheng, Sunny Lihua; Klaassen, Curtis D et al. (2016) Regulation of Hepatic Drug-Metabolizing Enzymes in Germ-Free Mice by Conventionalization and Probiotics. Drug Metab Dispos 44:262-74
Dzierlenga, Anika L; Clarke, John D; Klein, David M et al. (2016) Biliary Elimination of Pemetrexed Is Dependent on Mrp2 in Rats: Potential Mechanism of Variable Response in Nonalcoholic Steatohepatitis. J Pharmacol Exp Ther 358:246-53
Lu, Hong (2016) Crosstalk of HNF4α with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids. Acta Pharm Sin B 6:393-408
Peng, Lai; Piekos, Stephanie; Guo, Grace L et al. (2016) Role of farnesoid X receptor in establishment of ontogeny of phase-I drug metabolizing enzyme genes in mouse liver. Acta Pharm Sin B 6:453-459

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