|
1
|
Liu JJ, Mei HW, Jing YY, Li ZL, Wu SG, Yuan HX, Zhang XB. Yinchenhao decoction alleviates obstructive jaundice liver injury by modulating epidermal growth factor receptor and constitutive androstane receptor signaling. World J Hepatol 2025; 17:101724. [DOI: 10.4254/wjh.v17.i3.101724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 01/18/2025] [Accepted: 03/04/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Yinchenhao decoction (YCHD) is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice (OJ). Although YCHD has demonstrated protective effects against liver damage, reduced apoptosis, and mitigated oxidative stress in OJ, the precise molecular mechanisms involved remain poorly understood.
AIM To investigate the beneficial effects of YCHD on OJ and elucidate the underlying mechanisms.
METHODS The active constituents of YCHD were identified using liquid chromatography-tandem mass spectrometry, and their potential targets for OJ treatment were predicted through network pharmacology. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. An OJ rat model was established by common bile duct ligation. Rats were divided into three groups: Sham surgery (S Group), model (O Group), and YCHD (Y Group). YCHD was administered to Group Y for one week. Bilirubin levels, liver function parameters, and bile acid concentrations in blood and urine were measured by enzyme-linked immunosorbent assay. The bile acid renal clearance rate (Clr) was calculated. Histopathological evaluation of liver and kidney tissues was performed using hematoxylin-eosin staining. Western blotting was utilized to assess the expression of key bile acid metabolism and transport proteins in both liver and kidney tissues. The expression of the constitutive androstane receptor (CAR) and its nuclear localization were evaluated by immunohistochemistry. Molecular docking studies identified the epidermal growth factor receptor (EGFR) as a potential target of YCHD's active components. An OJ cell model was created using human liver (L02) and renal tubular epithelial (HK-2) cells, which were treated with YCHD-containing serum. Western blotting and immunofluorescence assays were employed to evaluate CAR expression and its nuclear localization in relation to EGFR activation.
RESULTS Network analysis identified the EGFR signaling pathway as a key mechanism through which YCHD exerts its effects on OJ. In vivo experiments showed that YCHD improved liver function, reduced OJ-induced pathology in liver and kidney tissues, and decreased serum bile acid content by enhancing bile acid Clr and urine output. YCHD also increased CAR expression and nuclear heterotopy, upregulating proteins involved in bile acid metabolism and transport, including CYP3A4, UGT1A1, MRP3, and MRP4 in the liver, and MRP2 and MRP4 in the kidneys. In vitro, YCHD increased CAR expression and nuclear heterotopy in L02 and HK-2 cells, an effect that was reversed by EGFR agonists.
CONCLUSION YCHD enhances bile acid metabolism in the liver and promotes bile acid excretion in the kidneys, ameliorating liver damage caused by OJ. These effects are likely mediated by the upregulation of CAR and its nuclear translocation.
Collapse
Affiliation(s)
- Jun-Jian Liu
- Department of Hepatobiliary and Pancreatic Surgery 2, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300102, China
- Tianjin Key Laboratory, Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin 300102, China
| | - Han-Wei Mei
- Department of Gastrointestinal Surgery 3, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 301617, China
| | - Yan-Yan Jing
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Zhong-Lian Li
- Department of Hepatobiliary and Pancreatic Surgery 2, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300102, China
| | - Su-Guo Wu
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Hong-Xia Yuan
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xi-Bo Zhang
- Department of Hepatobiliary and Pancreatic Surgery 2, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300102, China
| |
Collapse
|
|
2
|
Kim H, Park HJ. Current hPSC-derived liver organoids for toxicity testing: Cytochrome P450 enzymes and drug metabolism. Toxicol Res 2025; 41:105-121. [PMID: 40013078 PMCID: PMC11850699 DOI: 10.1007/s43188-024-00275-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 12/04/2024] [Accepted: 12/11/2024] [Indexed: 02/28/2025] Open
Abstract
Drug-induced hepatotoxicity is the leading cause of attrition of drug candidates and withdrawal of marketed drugs owing to safety concerns. In most hepatotoxicity cases, the parent drugs are metabolized by cytochrome P450 (CYP) enzymes, generating reactive metabolites that bind to intracellular organelles and proteins, ultimately causing hepatocellular damage. A major limitation of animal models, which are widely used for toxicity assessment, is the discrepancy in CYP-mediated drug metabolism and toxicological outcomes owing to species differences between humans and animals. Two-dimensional (2D) hepatocytes were first developed as a promising alternative model using human pluripotent stem cells (hPSCs). However, their CYP expression was similar to that of the fetal liver, and they lacked CYP-mediated hepatic metabolism. CYP expression in hPSC-derived hepatic models is closely correlated with liver maturity. Therefore, liver organoids that are more mature than hPSC-derived hepatic models and mimic the structure and physiological functions of the human liver have emerged as new alternatives. In this review, we explored the role and essentiality of CYPs in human hepatotoxicity, their expression, and epigenetic regulation in hPSC-derived hepatocytes and liver organoids, as well as the current state of liver organoid technology in terms of CYP expression and activity, drug metabolism, and toxicity. We also discussed the current challenges and future directions for the practical use of liver organoids. In conclusion, we highlight the importance of methods and metrics for accurately assessing CYP expression and activity in liver organoids to enable the development of feasible models that reproduce hepatotoxicity in humans.
Collapse
Affiliation(s)
- Hyemin Kim
- Division of Advanced Predictive Research, Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Han-Jin Park
- Division of Advanced Predictive Research, Korea Institute of Toxicology, Daejeon, Republic of Korea
| |
Collapse
|
|
3
|
Collins JM, Wang D. DNA Methylation in the CYP3A Distal Regulatory Region (DRR) Is Associated with the Expression of CYP3A5 and CYP3A7 in Human Liver Samples. Molecules 2024; 29:5407. [PMID: 39598796 PMCID: PMC11596782 DOI: 10.3390/molecules29225407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 11/13/2024] [Accepted: 11/15/2024] [Indexed: 11/29/2024] Open
Abstract
CYP3As are important drug-metabolizing enzymes in the liver. The causes for large inter-person variability in CYP3A expression/activity remain poorly understood. DNA methylation broadly regulates gene expression and the developmental transition from fetal CYP3A7 to adult CYP3A4, and CpG methylation upstream of the CYP3A4 promoter is associated with its expression. However, because non-promoter CYP3A regulatory regions remain largely uncharacterized, how DNA methylation influences CYP3A expression has yet to be fully explored. We recently identified a distal regulatory region (DRR) that controls the expression of CYP3A4, CYP3A5, and CYP3A7. Here, we investigated the relationship between CYP3A expression and the methylation status of 16 CpG sites within the DRR in 70 liver samples. We found significant associations between DRR methylation and the expression of CYP3A5 and CYP3A7 but not CYP3A4, indicating differential CYP3A regulation by the DRR. Also, we observed a dynamic reduction in DRR DNA methylation during the differentiation of induced pluripotent stem cells to hepatocytes, which correlated with increased CYP3A expression. We then evaluated the relative contribution of genetic variants, TFs, and DRR DNA methylation on CYP3A expression in liver samples. Our results reinforce the DRR as a CYP3A regulator and suggest that DNA methylation may impact CYP3A-mediated drug metabolism.
Collapse
Affiliation(s)
| | - Danxin Wang
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, FL 32610, USA;
| |
Collapse
|
|
4
|
Parvez MM, Thakur A, Mehrotra A, Stancil S, Pearce RE, Basit A, Leeder JS, Prasad B. Age-Dependent Abundance of CYP450 Enzymes Involved in Metronidazole Metabolism: Application to Pediatric PBPK Modeling. Clin Pharmacol Ther 2024; 116:1090-1099. [PMID: 38955794 DOI: 10.1002/cpt.3354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 06/16/2024] [Indexed: 07/04/2024]
Abstract
The expression of cytochrome P450 (CYP) enzymes is highly variable and associated with factors, such as age, genotype, sex, and disease states. In this study, quantification of metronidazole metabolizing CYP isoforms (CYP2A6, CYP2E1, CYP3A4, CYP3A5, and CYP3A7) in human liver microsomes from 115 children and 35 adults was performed using a quantitative proteomics method. The data confirmed age-dependent increase in CYP2A6, CYP2E1, and CYP3A4 abundance, whereas, as expected, CYP3A7 abundance showed postnatal decrease with age. In particular, the fold difference (neonatal to adulthood levels) in the protein abundance of CYP2A6, CYP2E1, and CYP3A4 was 14, 11, and 20, respectively. In contrast, protein abundance of CYP3A7 was > 125-fold higher in the liver microsomes of neonates than of adults. The abundance of CYP2A6 and CYP3A5 was associated with genotypes, rs4803381 and rs776746, respectively. A proteomics-informed physiologically based pharmacokinetic (PBPK) model was developed to describe the pharmacokinetics of metronidazole and its primary metabolite, 2-hydroxymethylmetronidazole. The model revealed an increase in the metabolite-to-parent ratio with age and showed a strong correlation between CYP2A6 abundance and metabolite formation (r 2 = 0.75). Notably, the estimated contribution of CYP3A7 was ~ 75% in metronidazole clearance in neonates. These data suggest that variability in CYP2A6 and CYP3A7 in younger children poses the risk of variable pharmacokinetics of metronidazole and its active metabolite with a potential impact on drug efficacy and safety. No sex-dependent difference was observed in the protein abundance of the studied CYPs. The successful integration of hepatic CYP ontogeny data derived from a large liver bank into the pediatric PBPK model of metronidazole can be extended to other drugs metabolized by the studied CYPs.
Collapse
Affiliation(s)
- Md Masud Parvez
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA
| | - Aarzoo Thakur
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA
| | - Aanchal Mehrotra
- Department of Pharmaceutics, University of Washington, Seattle, Washington, USA
| | - Stephani Stancil
- Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy-Kansas City, Kansas City, Missouri, USA
- School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Robin E Pearce
- Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy-Kansas City, Kansas City, Missouri, USA
- School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Abdul Basit
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA
| | - J Steven Leeder
- Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy-Kansas City, Kansas City, Missouri, USA
- School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Bhagwat Prasad
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA
| |
Collapse
|
|
5
|
Jin J, Zhong XB. Epigenetic Mechanisms Contribute to Intraindividual Variations of Drug Metabolism Mediated by Cytochrome P450 Enzymes. Drug Metab Dispos 2023; 51:672-684. [PMID: 36973001 PMCID: PMC10197210 DOI: 10.1124/dmd.122.001007] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 02/24/2023] [Accepted: 03/23/2023] [Indexed: 03/29/2023] Open
Abstract
Significant interindividual and intraindividual variations on cytochrome P450 (CYP)-mediated drug metabolism exist in the general population globally. Genetic polymorphisms are one of the major contribution factors for interindividual variations, but epigenetic mechanisms mainly contribute to intraindividual variations, including DNA methylation, histone modifications, microRNAs, and long non-coding RNAs. The current review provides analysis of advanced knowledge in the last decade on contributions of epigenetic mechanisms to intraindividual variations on CYP-mediated drug metabolism in several situations, including (1) ontogeny, the developmental changes of CYP expression in individuals from neonates to adults; (2) increased activities of CYP enzymes induced by drug treatment; (3) increased activities of CYP enzymes in adult ages induced by drug treatment at neonate ages; and (4) decreased activities of CYP enzymes in individuals with drug-induced liver injury (DILI). Furthermore, current challenges, knowledge gaps, and future perspective of the epigenetic mechanisms in development of CYP pharmacoepigenetics are discussed. In conclusion, epigenetic mechanisms have been proven to contribute to intraindividual variations of drug metabolism mediated by CYP enzymes in age development, drug induction, and DILI conditions. The knowledge has helped understanding how intraindividual variation are generated. Future studies are needed to develop CYP-based pharmacoepigenetics to guide clinical applications for precision medicine with improved therapeutic efficacy and reduced risk of adverse drug reactions and toxicity. SIGNIFICANCE STATEMENT: Understanding epigenetic mechanisms in contribution to intraindividual variations of CYP-mediated drug metabolism may help to develop CYP-based pharmacoepigenetics for precision medicine to improve therapeutic efficacy and reduce adverse drug reactions and toxicity for drugs metabolized by CYP enzymes.
Collapse
Affiliation(s)
- Jing Jin
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| | - Xiao-Bo Zhong
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
| |
Collapse
|
|
6
|
Hao X, Li Y, Bian J, Zhang Y, He S, Yu F, Feng Y, Huang L. Impact of DNA methylation on ADME gene expression, drug disposition and efficacy. Drug Metab Rev 2022; 54:194-206. [PMID: 35412942 DOI: 10.1080/03602532.2022.2064488] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Interindividual differences in drug response have always existed in clinical treatment. Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) play an important role in the process of pharmacokinetics. The effects of genetic polymorphism and nuclear receptors on the expression of drug metabolism enzymes and transporters can only explain some individual differences in clinical treatment. Several key ADME genes have been demonstrated to be regulated by epigenetic mechanisms that can potentially affect interindividual variability in medical treatment. Emerging studies have focused on the importance of DNA methylation for ADME gene expression and for drug response. Among them, the most studied is anti-tumor drugs, and followed by anti-tuberculous and anti-platelet drugs. Therefore, we provide an epigenetics perspective on variability in drug response. The review summarizes the correlation between ADME gene expression and DNA methylation, including the exact methylation locations, and focuses on the corresponding drug disposition and effects to illuminate interindividual differences in clinical medication.
Collapse
Affiliation(s)
- Xu Hao
- Department of Pharmacy, Peking University People's Hospital, Beijing, 100044 China.,School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Yuanyuan Li
- Department of Pharmacy, Peking University People's Hospital, Beijing, 100044 China.,School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Jialu Bian
- Department of Pharmacy, Peking University People's Hospital, Beijing, 100044 China
| | - Ying Zhang
- Department of Pharmacy, Peking University People's Hospital, Beijing, 100044 China
| | - Shiyu He
- Department of Pharmacy, Peking University People's Hospital, Beijing, 100044 China
| | - Feng Yu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Yufei Feng
- Department of Pharmacy, Peking University People's Hospital, Beijing, 100044 China
| | - Lin Huang
- Department of Pharmacy, Peking University People's Hospital, Beijing, 100044 China
| |
Collapse
|
|
7
|
Abstract
Almost 50% of prescription drugs lack age-appropriate dosing guidelines and therefore are used "off-label." Only ~10% drugs prescribed to neonates and infants have been studied for safety or efficacy. Immaturity of drug metabolism in children is often associated with drug toxicity. This chapter summarizes data on the ontogeny of major human metabolizing enzymes involved in oxidation, reduction, hydrolysis, and conjugation of drugs. The ontogeny data of individual drug-metabolizing enzymes are important for accurate prediction of drug pharmacokinetics and toxicity in children. This information is critical for designing clinical studies to appropriately test pharmacological hypotheses and develop safer pediatric drugs, and to replace the long-standing practice of body weight- or surface area-normalized drug dosing. The application of ontogeny data in physiologically based pharmacokinetic model and regulatory submission are discussed.
Collapse
|
|
8
|
Collins JM, Wang D. Co-expression of drug metabolizing cytochrome P450 enzymes and estrogen receptor alpha (ESR1) in human liver: racial differences and the regulatory role of ESR1. Drug Metab Pers Ther 2021; 36:205-214. [PMID: 33823094 DOI: 10.1515/dmpt-2020-0160] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 01/03/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVES The function and expression of cytochrome P450 (CYP) drug metabolizing enzymes is highly variable, greatly affecting drug exposure, and therapeutic outcomes. The expression of these enzymes is known to be controlled by many transcription factors (TFs), including ligand-free estrogen receptor alpha (ESR1, in the absence of estrogen). However, the relationship between the expression of ESR1, other TFs, and CYP enzymes in human liver is still unclear. METHODS Using real-time PCR, we quantified the mRNA levels of 12 CYP enzymes and nine TFs in 246 human liver samples from European American (EA, n = 133) and African American (AA, n = 113) donors. RESULTS Our results showed higher expression levels of ESR1 and six CYP enzymes in EA than in AA. Partial least square regression analysis showed that ESR1 is the top-ranking TF associating with the expression of eight CYP enzymes, six of which showed racial difference in expression. Conversely, four CYP enzymes without racial difference in expression did not have ESR1 as a top-ranking TF. These results indicate that ESR1 may contribute to variation in CYP enzyme expression between these two ancestral backgrounds. CONCLUSIONS These results are consistent with our previous study showing ESR1 as a master regulator for the expression of several CYP enzymes. Therefore, factors affecting ESR1 expression may have broad influence on drug metabolism through altered expression of CYP enzymes.
Collapse
Affiliation(s)
- Joseph M Collins
- Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Danxin Wang
- Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| |
Collapse
|
|
9
|
Chapron BD, Chapron A, Leeder JS. Recent advances in the ontogeny of drug disposition. Br J Clin Pharmacol 2021; 88:4267-4284. [PMID: 33733546 DOI: 10.1111/bcp.14821] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 02/12/2021] [Accepted: 02/22/2021] [Indexed: 12/11/2022] Open
Abstract
Developmental changes that occur throughout childhood have long been known to impact drug disposition. However, pharmacokinetic studies in the paediatric population have historically been limited due to ethical concerns arising from incorporating children into clinical trials. As such, much of the early work in the field of developmental pharmacology was reliant on difficult-to-interpret in vitro and in vivo animal studies. Over the last 2 decades, our understanding of the mechanistic processes underlying age-related changes in drug disposition has advanced considerably. Progress has largely been driven by technological advances in mass spectrometry-based methods for quantifying proteins implicated in drug disposition, and in silico tools that leverage these data to predict age-related changes in pharmacokinetics. This review summarizes our current understanding of the impact of childhood development on drug disposition, particularly focusing on research of the past 20 years, but also highlighting select examples of earlier foundational research. Equally important to the studies reviewed herein are the areas that we cannot currently describe due to the lack of research evidence; these gaps provide a map of drug disposition pathways for which developmental trends still need to be characterized.
Collapse
Affiliation(s)
- Brian D Chapron
- Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, USA
| | - Alenka Chapron
- Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, USA
| | - J Steven Leeder
- Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, USA.,Schools of Medicine and Pharmacy, University of Missouri-Kansas City, MO, USA
| |
Collapse
|
|
10
|
Naji-Talakar S, Sharma S, Martin LA, Barnhart D, Prasad B. Potential implications of DMET ontogeny on the disposition of commonly prescribed drugs in neonatal and pediatric intensive care units. Expert Opin Drug Metab Toxicol 2021; 17:273-289. [PMID: 33256492 PMCID: PMC8346204 DOI: 10.1080/17425255.2021.1858051] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 11/27/2020] [Indexed: 10/22/2022]
Abstract
Introduction: Pediatric patients, especially neonates and infants, are more susceptible to adverse drug events as compared to adults. In particular, immature small molecule drug metabolism and excretion can result in higher incidences of pediatric toxicity than adults if the pediatric dose is not adjusted.Area covered: We reviewed the top 29 small molecule drugs prescribed in neonatal and pediatric intensive care units and compiled the mechanisms of their metabolism and excretion. The ontogeny of Phase I and II drug metabolizing enzymes and transporters (DMETs), particularly relevant to these drugs, are summarized. The potential effects of DMET ontogeny on the metabolism and excretion of the top pediatric drugs were predicted. The current regulatory requirements and recommendations regarding safe and effective use of drugs in children are discussed. A few representative examples of the use of ontogeny-informed physiologically based pharmacokinetic (PBPK) models are highlighted.Expert opinion: Empirical prediction of pediatric drug dosing based on body weight or body-surface area from the adult parameters can be inaccurate because DMETs are not mature in children and the age-dependent maturation of these proteins is different. Ontogeny-informed-PBPK modeling provides a better alternative to predict the pharmacokinetics of drugs in children.
Collapse
Affiliation(s)
- Siavosh Naji-Talakar
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, USA
| | - Sheena Sharma
- Pediatrics and Neonatology, Providence Sacred Heart Medical Center and Children’s Hospital, Spokane, WA, USA
| | - Leslie A. Martin
- Pediatrics and Neonatology, Providence Sacred Heart Medical Center and Children’s Hospital, Spokane, WA, USA
| | - Derek Barnhart
- Pediatrics and Neonatology, Providence Sacred Heart Medical Center and Children’s Hospital, Spokane, WA, USA
| | - Bhagwat Prasad
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, USA
| |
Collapse
|
|
11
|
Peedicayil J. Pharmacoepigenetics and Pharmacoepigenomics: An Overview. Curr Drug Discov Technol 2020; 16:392-399. [PMID: 29676232 DOI: 10.2174/1570163815666180419154633] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 04/04/2018] [Accepted: 04/05/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND The rapid and major advances being made in epigenetics are impacting pharmacology, giving rise to new sub-disciplines in pharmacology, pharmacoepigenetics, the study of the epigenetic basis of variation in response to drugs; and pharmacoepigenomics, the application of pharmacoepigenetics on a genome-wide scale. METHODS This article highlights the following aspects of pharmacoepigenetics and pharmacoepigenomics: epigenetic therapy, the role of epigenetics in pharmacokinetics, the relevance of epigenetics to adverse drug reactions, personalized medicine, drug addiction, and drug resistance, and the use of epigenetic biomarkers in drug therapy. RESULTS Epigenetics is having an increasing impact on several areas of pharmacology. CONCLUSION Pharmacoepigenetics and pharmacoepigenomics are new sub-disciplines in pharmacology and are likely to have an increasing impact on the use of drugs in clinical practice.
Collapse
Affiliation(s)
- Jacob Peedicayil
- Department of Pharmacology & Clinical Pharmacology, Christian Medical College, Vellore, India
| |
Collapse
|
|
12
|
Li H, Lampe JN. Neonatal cytochrome P450 CYP3A7: A comprehensive review of its role in development, disease, and xenobiotic metabolism. Arch Biochem Biophys 2019; 673:108078. [PMID: 31445893 DOI: 10.1016/j.abb.2019.108078] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 08/17/2019] [Accepted: 08/18/2019] [Indexed: 12/14/2022]
Abstract
The human cytochrome P450 CYP3A7, once thought to be an enzyme exclusive to fetal livers, has more recently been identified in neonates and developing infants as old as 24 months post-gestational age. CYP3A7 has been demonstrated to metabolize two endogenous compounds that are known to be important in the growth and development of the fetus and neonate, namely dehydroepiandrosterone sulfate (DHEA-S) and all-trans retinoic acid (atRA). In addition, it is also known to metabolize a variety of drugs and xenobiotics, albeit generally to a lesser extent relative to CYP3A4/5. CYP3A7 is an important component in the development and protection of the fetal liver and additionally plays a role in certain disease states, such as cancer and adrenal hyperplasia. Ultimately, a full understanding of the expression, regulation, and metabolic properties of CYP3A7 is needed to provide neonates with appropriate individualized pharmacotherapy. This article summarizes the current state of knowledge of CYP3A7, including its discovery, distribution, alleles, RNA splicing, expression and regulation, metabolic properties, substrates, and inhibitors.
Collapse
Affiliation(s)
- Haixing Li
- Sino-German Joint Research Institute Nanchang University, 235 East Nanjing Road, Nanchang, 330047, Jiangxi, PR China
| | - Jed N Lampe
- University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Mail Stop C238, 12850 E. Montview Blvd., Aurora, CO, 80045, USA.
| |
Collapse
|
|
13
|
Dempsey JL, Cui JY. Regulation of Hepatic Long Noncoding RNAs by Pregnane X Receptor and Constitutive Androstane Receptor Agonists in Mouse Liver. Drug Metab Dispos 2019; 47:329-339. [PMID: 30593543 PMCID: PMC6382996 DOI: 10.1124/dmd.118.085142] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 12/21/2018] [Indexed: 12/28/2022] Open
Abstract
Altered expression of long noncoding RNAs (lncRNAs) by environmental chemicals modulates the expression of xenobiotic biotransformation-related genes and may serve as therapeutic targets and novel biomarkers of exposure. The pregnane X receptor (PXR/NR1I2) is a critical xenobiotic-sensing nuclear receptor that regulates the expression of many drug-processing genes, and it has similar target-gene profiles and DNA-binding motifs with another xenobiotic-sensing nuclear receptor, namely, constitutive andronstrane receptor (CAR/Nr1i3). To test our hypothesis that lncRNAs are regulated by PXR in concert with protein-coding genes (PCGs) and to compare the PXR-targeted lncRNAs with CAR-targeted lncRNAs, RNA-Seq was performed from livers of adult male C57BL/6 mice treated with corn oil, the PXR agonist PCN, or the CAR agonist 1, 4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). Among 125,680 known lncRNAs, 3843 were expressed in liver, and 193 were differentially regulated by PXR (among which 40% were also regulated by CAR). Most PXR- or CAR-regulated lncRNAs were mapped to the introns and 3'-untranslated regions (UTRs) of PCGs, as well as intergenic regions. Combining the RNA-Seq data with a published PXR chromatin immunoprecipitation coupled with high-throughput sequencing; cytochrome P450 (P450; ChIP-Seq) data set, we identified 774 expressed lncRNAs with direct PXR-DNA binding sites, and 26.8% of differentially expressed lncRNAs had changes in PXR-DNA binding after PCN exposure. De novo motif analysis identified colocalization of PXR with liver receptor homolog (LRH-1), which regulates bile acid synthesis after PCN exposure. There was limited overlap of PXR binding with an epigenetic mark for transcriptional activation (histone-H3K4-di-methylation, H3K4me2) but no overlap with epigenetic marks for transcriptional silencing [H3 lysine 27 tri-methylation (H3K27me3) and DNA methylation]. Among differentially expressed lncRNAs, 264 were in proximity of PCGs, and the lncRNA-PCG pairs displayed a high coregulatory pattern by PXR and CAR activation. This study was among the first to demonstrate that lncRNAs are regulated by PXR and CAR activation and that they may be important regulators of PCGs involved in xenobiotic metabolism.
Collapse
Affiliation(s)
- Joseph L Dempsey
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
| |
Collapse
|
|
14
|
Bhatt DK, Prasad B. Critical Issues and Optimized Practices in Quantification of Protein Abundance Level to Determine Interindividual Variability in DMET Proteins by LC-MS/MS Proteomics. Clin Pharmacol Ther 2017; 103:619-630. [PMID: 28833066 DOI: 10.1002/cpt.819] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 07/24/2017] [Accepted: 08/12/2017] [Indexed: 12/16/2022]
Abstract
Protein quantification data on drug metabolizing enzymes and transporters (collectively referred as DMET proteins) in human tissues are useful in predicting interindividual variability in drug disposition. While targeted proteomics is an emerging technique for quantification of DMET proteins, the methodology involves significant technical challenges especially when multiple samples are analyzed in a single study over a long period of time. Therefore, it is important to thoroughly address the critical variables that could affect DMET protein quantification.
Collapse
Affiliation(s)
- Deepak Kumar Bhatt
- Department of Pharmaceutics, University of Washington, Seattle, Washington, USA
| | - Bhagwat Prasad
- Department of Pharmaceutics, University of Washington, Seattle, Washington, USA
| |
Collapse
|
|
15
|
Developmental regulation of CYP3A4 and CYP3A7 in Chinese Han population. Drug Metab Pharmacokinet 2016; 31:433-444. [PMID: 27727071 DOI: 10.1016/j.dmpk.2016.08.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 07/12/2016] [Accepted: 08/30/2016] [Indexed: 01/06/2023]
Abstract
CYP3A4 and CYP3A7 are generally served as the major adult and fetal liver forms, respectively, and exhibited a developmental switch during liver maturation. The objective of this study was to explore the potential mechanisms associated with the developmental switch of CYP3A4 and CYP3A7 in the Chinese Han population. We analyzed CYP3A4/7, nuclear receptors, and epigenetic modifications in human liver samples. We found that the expression levels of CYP3A4 mRNA in adults were significantly higher than the levels in fetus. In contrast, CYP3A7 mRNA expression reached a maximal level at an estimated gestational age of 25 weeks and then substantially decreased during the first year after birth. We also found that the expression level of hepatocyte nuclear factor 4 alpha (HNF4A) was most associated with CYP3A4 expression in adult liver; whereas the expression level of glucocorticoid receptor (GR) was intensively correlated with CYP3A7 expression in fetal liver. Furthermore, we illustrated the dynamic changes of H3K4me2 and H3K27me3 in the developmental switch of CYP3A7 and CYP3A4. In summary, our data suggested that HNF4A and GR, and epigenetic changes of H3K4me2 and H3K27me3 are associated with the ontogenic expressions of CYP3A4/3A7 in the livers of the Chinese Han population.
Collapse
|
|
16
|
Leeder JS, Meibohm B. Challenges and Opportunities for Increasing the Knowledge Base Related to Drug Biotransformation and Pharmacokinetics during Growth and Development. Drug Metab Dispos 2016; 44:916-23. [PMID: 27302933 DOI: 10.1124/dmd.116.071159] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 05/11/2016] [Indexed: 01/22/2023] Open
Abstract
It is generally acknowledged that there is a need and role for informative pharmacokinetic models to improve predictions and simulation as well as individualization of drug therapy in pediatric populations of different ages and developmental stages. This special issue contains more than 20 papers responding to the challenge of providing new information on scaling factors, ontogeny functions for drug metabolizing enzymes and transporters, the mechanisms underlying the observed developmental trajectories for these gene products, age-dependent changes in physiologic processes affecting drug disposition in children, as well as in vitro and in vivo studies describing the relative contribution of ontogeny and genetic factors as sources of variability in drug disposition in children. Considered together, these contributions serve to illustrate some of the current limitations regarding sample availability, number, and quality, but also provide a framework that allows for the potential value of the results of a given study to be interpreted within the context of these limitations. Among the challenges for the future are improving our understanding of the mechanisms regulating age-dependent changes in factors influencing drug disposition and response, thereby facilitating generalization to systems lacking detailed data, better integrating age-dependent changes in pharmacokinetics with age-dependent changes in pharmacodynamics, and allowing better predictability and individualization of drug disposition and response across the pediatric age spectrum.
Collapse
Affiliation(s)
- J Steven Leeder
- Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospitals and Clinics, University of Missouri-Kansas City, Kansas City, Missouri (J.S.L.); and Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee (B.M.)
| | - Bernd Meibohm
- Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospitals and Clinics, University of Missouri-Kansas City, Kansas City, Missouri (J.S.L.); and Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee (B.M.)
| |
Collapse
|