Ontogeny-related pharmacogene changes in the pediatric liver transcriptome

Meier, Richard; Bi, Chengpeng; Gaedigk, Roger; Heruth, Daniel P.; Ye, Shui Qing; Leeder, J. Steven; Fridley, Brooke L.

doi:10.1097/fpc.0000000000000326

Cited by 8 publications

(4 citation statements)

References 28 publications

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“…For example, in the United States, availability of tissue samples from infants <1 year of age is relatively infrequent, and those that are available for research tend to be procured from the NIH-funded University of Maryland Brain and Tissue Bank for Developmental Disorders. This period of time also tends to be a period of rapid growth and can be accompanied by developmental patterns of gene expression as we noted in a previous study involving RNA-Seq analysis of a similar set of samples (17). Thus, it is difficult to differentiate true developmental differences in RNA or metabolite expression from confounding effects related to tissue source.…”

Section: Discussionmentioning

confidence: 91%

“…Thus, it is difficult to differentiate true developmental differences in RNA or metabolite expression from confounding effects related to tissue source. Given that initial statistical analysis of the metabolomic data corroborated the source effect in the RNA-Seq data (17), the current investigation included samples <1 year of age from a second, independent source. This experimental approach detected 24 metabolites that changed in a set of liver samples spanning birth to late adolescence (18 years of age; Table 2).…”

Section: Discussionmentioning

confidence: 99%

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Ontogeny Related Changes in the Pediatric Liver Metabolome

Wilson

Gaedigk

et al. 2020

Front. Pediatr.

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Background: A major challenge in implementing personalized medicine in pediatrics is identifying appropriate drug dosages for children. The majority of drug dosing studies have been based on adult populations, often with modification of the dosing for children based on size and weight. However, the growth and development experienced by children between birth and adulthood represents a dynamically changing biological system, with implications for effective drug dosing, efficacy as well as potential drug toxicity. The purpose of this study was to apply a metabolomics approach to gain preliminary insights into the ontogeny of liver function from newborn to adolescent. Methods: Metabolites were measured in 98 post-mortem pediatric liver samples in two experiments 3 batches of samples, allowing for both technical and biological validation. After extensive quality control, imputation and normalization, non-parametric tests were used to determine which metabolite levels differ between the four age groups (AG) ranging in age from newborn to adolescent (AG1-children <1 year; AG2-children with age between 1 and 6 years; AG3-children with age between 6 and 12 years; AG4-children with age between 12 and 18 years). To identify which metabolites had different concentration levels among the age groups, Kruskal-Wallis and Spearman correlation tests were conducted. Pathway analysis utilized the Gamma Method. Correction for multiple testing was completed using Bonferroni correction. Results: We found 41 metabolites (out of 884) that were biologically validated, and of those 25 were technically replicated, of which 24 were known metabolites. For the majority of these 24 metabolites, concentration levels were significantly lower in newborns than in the other age groups, many of which were long chain fatty acids or involved in pyrimidine or purine metabolism. Additionally, we found two KEGG pathways enriched for association with age: betaine metabolism and alpha linolenic acid and linoleic acid metabolism. Conclusions: Understanding the role that ontogeny of childhood liver plays may aid in determining better drug dosing algorithms for children.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Ontogeny Related Changes in the Pediatric Liver Metabolome

Wilson

Gaedigk

et al. 2020

Front. Pediatr.

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“…Moreover, the analysis of OCT1 expression in different types of liver lesions, together with that of other SLC22A family members, such as OCT3 (gene symbol SLC22A3), has been proposed as a diagnostic marker of intrahepatic lesions [14]. However, a recent study provides evidence for age-related changes in transcriptome liver profile for important drug-related genes, such as SLC22A1, whose expression was higher in the group of older people [15], thus requiring stratification for the use of these genes as biomarkers.…”

Section: Carriers As Biomarkersmentioning

confidence: 99%

Plasma Membrane Transporters as Biomarkers and Molecular Targets in Cholangiocarcinoma

Marin

Macı́as

Cives-Losada

et al. 2020

Cells

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The dismal prognosis of patients with advanced cholangiocarcinoma (CCA) is due, in part, to the extreme resistance of this type of liver cancer to available chemotherapeutic agents. Among the complex mechanisms accounting for CCA chemoresistance are those involving the impairment of drug uptake, which mainly occurs through transporters of the superfamily of solute carrier (SLC) proteins, and the active export of drugs from cancer cells, mainly through members of families B, C and G of ATP-binding cassette (ABC) proteins. Both mechanisms result in decreased amounts of active drugs able to reach their intracellular targets. Therefore, the “cancer transportome”, defined as the set of transporters expressed at a given moment in the tumor, is an essential element for defining the multidrug resistance (MDR) phenotype of cancer cells. For this reason, during the last two decades, plasma membrane transporters have been envisaged as targets for the development of strategies aimed at sensitizing cancer cells to chemotherapy, either by increasing the uptake or reducing the export of antitumor agents by modulating the expression/function of SLC and ABC proteins, respectively. Moreover, since some elements of the transportome are differentially expressed in CCA, their usefulness as biomarkers with diagnostic and prognostic purposes in CCA patients has been evaluated.

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“…The contribution factors must be beyond DNA sequences, normally referring to epigenetics (Bonasio et al, 2010). Epigenetics is the molecular events in response to 9 Stevens et al, 2008;Sadler et al, 2016;Meier et al, 2018). Three major patterns of developmental changes have been identified, which is summarized in Fig.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Mechanisms Contribute to Intraindividual Variations of Drug Metabolism Mediated by Cytochrome P450 Enzymes

Jin

Zhong

2023

Drug Metab Dispos

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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 (miRNAs), and long non-coding RNAs (lncRNAs). 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 (ADRs) and toxicity.

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Ontogeny-related pharmacogene changes in the pediatric liver transcriptome

Abstract: Supplemental Digital Content is available in the text.

Cited by 8 publications

References 28 publications

Ontogeny Related Changes in the Pediatric Liver Metabolome

Ontogeny Related Changes in the Pediatric Liver Metabolome

Plasma Membrane Transporters as Biomarkers and Molecular Targets in Cholangiocarcinoma

Epigenetic Mechanisms Contribute to Intraindividual Variations of Drug Metabolism Mediated by Cytochrome P450 Enzymes

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