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.
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.
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