The NIH Funding Opportunity PAR-13-306: Developmental Pharmacology and Toxicology: Role of Ontogeny emphasizes the urgency of addressing the issue of short- or long-term alterations of genes involved in pharmacokinetics in response to drug exposure in early development. Physicians use drugs to treat various diseases in neonates and infants. However, the current clinical practices have not considered the potential short- or long-term consequences on the patient's ability to metabolize drugs during adulthood who have received drug treatment early in life. A major reason is the lack of basic research to understand the consequences (short- or long-term) that drug exposure in early life has on drug metabolism, therapeutic efficacy, and potential for drug-induced toxicity. The goal in this study is to understand the short- or long-term impacts of drug exposure at early life on drug metabolism, therapeutic efficacy, and drug-induced toxicity. Based on the previous publications and our preliminary data, we have formed a central hypothesis that early life exposure to drugs that have the ability to activate nuclear receptors can result in either immediate (short-term) or persistent (long-term) alterations of expression and functions of certain drug metabolizing enzymes, further leading to alterations in therapeutic efficacy and sensitivity to toxicity of other drugs. This effect is dependent on the ability of the drug exposur with a certain dose at a specific age to alter epigenetic memory in liver. We have formed an investigator team with experts necessary to accomplish the proposed works. We will use phenobarbital for drug exposure at early life, omeprazole and midazolam for therapeutic efficacy, and acetaminophen for hepatotoxicity. We will focus on P450s (such as Cyp2b, Cyp2c, and Cyp3a) as our target drug metabolizing enzymes and the mouse as our animal model to examine the central hypothesis in the following specific aims.
Aim 1 will determine the short- or long-term impacts of drug exposure at early life on drug metabolism.
Aim 2 will determine the short- or long-term impacts of drug exposure at early life on therapeutic efficacy.
Aim 3 will determine the short- or long-term impacts of drug exposure at early life on drug-induced hepatotoxicity. After completion of the specific aims, we will fill the knowledge gaps on the short or long-term impacts of drug exposure at early life on drug metabolism. Such knowledge is critical for developmental pharmacology and toxicology to better predict outcomes of drug exposure at early ages on drug responses and sensitivity to drug-induced toxicity throughout the lifetime.

Public Health Relevance

The current application serves as a proof-of-concept study to determine the short- or long-term impacts of drug exposure at early life on drug metabolism, therapeutic efficacy, and drug-induced toxicity in animal models. Once the basic knowledge is established in animal models, the information can be used as a guide for clinical studies in humans to select the right drugs and appropriate ages of patients to evaluate the short- or long-term impacts of drug exposure at early life on drug therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM118367-01
Application #
9077520
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Okita, Richard T
Project Start
2016-04-01
Project End
2020-01-31
Budget Start
2016-04-01
Budget End
2017-01-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
614209054
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
Bao, Yifan; Ma, Xiaochao; Rasmussen, Theodore P et al. (2018) Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury. Curr Pharmacol Rep 4:171-181
Piekos, Stephanie C; Chen, Liming; Wang, Pengcheng et al. (2018) Consequences of Phenytoin Exposure on Hepatic Cytochrome P450 Expression during Postnatal Liver Maturation in Mice. Drug Metab Dispos 46:1241-1250
Chen, Liming; Bao, Yifan; Piekos, Stephanie C et al. (2018) A Transcriptional Regulatory Network Containing Nuclear Receptors and Long Noncoding RNAs Controls Basal and Drug-Induced Expression of Cytochrome P450s in HepaRG Cells. Mol Pharmacol 94:749-759
Kong, Bo; Sun, Runbin; Huang, Mingxing et al. (2018) Fibroblast Growth Factor 15-Dependent and Bile Acid-Independent Promotion of Liver Regeneration in Mice. Hepatology 68:1961-1976
Wang, Pengcheng; Sachar, Madhav; Guo, Grace L et al. (2018) Liver metabolomics in a mouse model of erythropoietic protoporphyria. Biochem Pharmacol 154:474-481
Yu, Ai-Ming; Ingelman-Sundberg, Magnus; Cherrington, Nathan J et al. (2017) Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota, and diseases: a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations (MDO). Acta Pharm Sin B 7:241-248
Prabhakar, Bindu; Zhong, Xiao-Bo; Rasmussen, Theodore P (2017) Exploiting Long Noncoding RNAs as Pharmacological Targets to Modulate Epigenetic Diseases. Yale J Biol Med 90:73-86
Pope, Chad; Mishra, Shashank; Russell, Joshua et al. (2017) Targeting H19, an Imprinted Long Non-Coding RNA, in Hepatic Functions and Liver Diseases. Diseases 5:
Yan, Liang; Wang, Yiting; Liu, Jingyang et al. (2017) Alterations of Histone Modifications Contribute to Pregnane X Receptor-Mediated Induction of CYP3A4 by Rifampicin. Mol Pharmacol 92:113-123
Tien, Yun-Chen; Piekos, Stephanie C; Pope, Chad et al. (2017) Phenobarbital Treatment at a Neonatal Age Results in Decreased Efficacy of Omeprazole in Adult Mice. Drug Metab Dispos 45:330-335

Showing the most recent 10 out of 17 publications