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 #
5R01ES019487-03
Application #
8274542
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
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$586,637
Indirect Cost
$195,546
Name
University of Kansas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Renaud, Helen J; Cui, Yue Julia; Lu, Hong et al. (2014) Ontogeny of hepatic energy metabolism genes in mice as revealed by RNA-sequencing. PLoS One 9:e104560
Renaud, Helen J; Cui, Julia Y; Lu, Hong et al. (2014) Effect of diet on expression of genes involved in lipid metabolism, oxidative stress, and inflammation in mouse liver-insights into mechanisms of hepatic steatosis. PLoS One 9:e88584
Lu, Yuan-Fu; Liu, Jie; Wu, Kai Connie et al. (2014) Overexpression of Nrf2 protects against microcystin-induced hepatotoxicity in mice. PLoS One 9:e93013
Zhang, Qinghao; Lei, Xiaohong; Lu, Hong (2014) Alterations of epigenetic signatures in hepatocyte nuclear factor 4? deficient mouse liver determined by improved ChIP-qPCR and (h)MeDIP-qPCR assays. PLoS One 9:e84925
Cheng, Xingguo; Vispute, Saurabh G; Liu, Jie et al. (2014) Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR). Toxicol Appl Pharmacol 278:65-71
Clarke, John D; Hardwick, Rhiannon N; Lake, April D et al. (2014) Synergistic interaction between genetics and disease on pravastatin disposition. J Hepatol 61:139-47
Zhang, Yu-Kun Jennifer; Wu, Kai Connie; Klaassen, Curtis D (2013) Genetic activation of Nrf2 protects against fasting-induced oxidative stress in livers of mice. PLoS One 8:e59122
Zhang, Yu-Kun Jennifer; Lu, Hong; Klaassen, Curtis D (2013) Expression of human CAR splicing variants in BAC-transgenic mice. Toxicol Sci 132:142-50
Zhang, Youcai; Klaassen, Curtis D (2013) Hormonal regulation of Cyp4a isoforms in mouse liver and kidney. Xenobiotica 43:1055-63
Ingelman-Sundberg, Magnus; Zhong, Xiao-Bo; Hankinson, Oliver et al. (2013) Potential role of epigenetic mechanisms in the regulation of drug metabolism and transport. Drug Metab Dispos 41:1725-31

Showing the most recent 10 out of 31 publications