The cytochrome P450 3A subfamily (CYP3A) members, such CYP3A4, CYP3A5, and CYP3A7, are the most abundant P450 enzymes expressed in human liver and intestine and are responsible for metabolizing >50% of drugs. Significant variations in CYP3A activity and gene expression have been found in liver during development, with infants and young children having different ability to metabolize many drugs than adults. Particularly, CYP3A4 and CYP3A7 exhibit profound reciprocal patterns of gene expression with a developmental switch after birth. However, the mechanisms governing the ontogenic expression of the CYP3A genes during development are unknown. Our long- term research goal is to unravel the mechanisms that control drug metabolism during development. The objective of this proposal is to identify the mechanisms controlling the ontogenic expression of the Cyp3a genes in livers during postnatal development by using mouse as a model. Our central hypothesis is that the ontogenic expression patterns of the Cyp3a genes in mouse liver are controlled by transcription factors which change epigenetic modifications at the target chromatin, and place the Cyp3a genes in distinct nuclear positions, allowing the Cyp3a genes to be turned on or off at different developmental stages. To test this hypothesis, we propose to pursue the following specific aims: (1) to establish profiles of histone modifications around the Cyp3a genes in liver cells at different ages;(2) to define chromatin condensation, nuclear positions, and associated histone modifications of the Cyp3a genes in hepatocyte nuclei at different ages;and (3) to examine the roles of the transcription factors in controlling ontogenic expression of the Cyp3a genes during liver maturation. We have assembled a multidisciplinary team and have all the techniques and mouse models ready for the proposed studies, which will help to ensure a successful completion of the proposed studies. If we prove our hypothesis is correct, the proposed study will identify transcription factors which control the ontogenic expression of the Cyp3a genes through epigenetic mechanisms. It would add greatly to our fundamental knowledge of developmental regulation of gene expression in liver development. This knowledge is particularly novel for drug metabolizing enzymes, because the areas of epigenetics and gene positioning have not received much attention with respect to the ontogeny of genes involved in drug biotransformation. Establishment of this fundamental knowledge is essential for understanding difference of drug responses between pediatric and adult patients and is important for establishing pharmaco-epigenomics based on inter-individual variation of epigenomes in personalized medicine.

Public Health Relevance

The proposed research is important for establishing the general mechanisms controlling ontogenic gene expression of drug metabolizing enzymes in liver during early postnatal ages. This fundamental knowledge will help us to understand why children have different ability to metabolize drugs than adults.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM087376-06
Application #
8605879
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
6
Fiscal Year
2014
Total Cost
$311,435
Indirect Cost
$113,435
Name
University of Connecticut
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
614209054
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269
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
Peng, Lai; Cui, Julia Y; Yoo, Byunggil et al. (2013) RNA-sequencing quantification of hepatic ontogeny of phase-I enzymes in mice. Drug Metab Dispos 41:2175-86
Zhong, Xiao-bo; Leeder, J Steven (2013) Epigenetic regulation of ADME-related genes: focus on drug metabolism and transport. Drug Metab Dispos 41:1721-4
Peng, Lai; Yoo, Byunggil; Gunewardena, Sumedha S et al. (2012) RNA sequencing reveals dynamic changes of mRNA abundance of cytochromes P450 and their alternative transcripts during mouse liver development. Drug Metab Dispos 40:1198-209
Li, Dan; Gaedigk, Roger; Hart, Steven N et al. (2012) The role of CYP3A4 mRNA transcript with shortened 3'-untranslated region in hepatocyte differentiation, liver development, and response to drug induction. Mol Pharmacol 81:86-96
Hart, Steven N; Li, Ye; Nakamoto, Kaori et al. (2010) A comparison of whole genome gene expression profiles of HepaRG cells and HepG2 cells to primary human hepatocytes and human liver tissues. Drug Metab Dispos 38:988-94