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Role of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny.

ABSTRACT: Variability in drug-metabolizing enzyme developmental trajectories contributes to interindividual differences in susceptibility to chemical toxicity and adverse drug reactions, particularly in the first years of life. Factors linked to these interindividual differences are largely unknown, but molecular mechanisms regulating ontogeny are likely involved. To evaluate chromatin structure dynamics as a likely contributing mechanism, age-dependent changes in modified and variant histone occupancy were evaluated within known CYP3A4 and 3A7 regulatory domains. Chromatin immunoprecipitation using fetal or postnatal human hepatocyte chromatin pools followed by quantitative polymerase chain reaction DNA amplification was used to determine relative chromatin occupancy by modified and variant histones. Chromatin structure representing a poised transcriptional state (bivalent chromatin), indicated by the occupancy by modified histones associated with both active and repressed transcription, was observed for CYP3A4 and most 3A7 regulatory regions in both postnatal and fetal livers. However, the CYP3A4 regulatory regions had significantly greater occupancy by modified histones associated with repressed transcription in the fetal liver. Conversely, some modified histones associated with active transcription exhibited greater occupancy in the postnatal liver. CYP3A7 regulatory regions also had significantly greater occupancy by modified histones associated with repressed transcription in the fetus. The observed occupancy by modified histones is consistent with chromatin structural dynamics contributing to CYP3A4 ontogeny, although the data are less conclusive regarding CYP3A7. Interpretation of the latter data may be confounded by cell-type heterogeneity in the fetal liver.

SUBMITTER: Giebel NL

PROVIDER: S-EPMC4931893 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other

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Role of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny.

Giebel Nicholas L NL Shadley Jeffrey D JD McCarver D Gail DG Dorko Kenneth K Gramignoli Roberto R Strom Stephen C SC Yan Ke K Simpson Pippa M PM Hines Ronald N RN

Drug metabolism and disposition: the biological fate of chemicals 20160226 7

Variability in drug-metabolizing enzyme developmental trajectories contributes to interindividual differences in susceptibility to chemical toxicity and adverse drug reactions, particularly in the first years of life. Factors linked to these interindividual differences are largely unknown, but molecular mechanisms regulating ontogeny are likely involved. To evaluate chromatin structure dynamics as a likely contributing mechanism, age-dependent changes in modified and variant histone occupancy we ...[more]

PMID: 26921389

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Project description: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.

Dataset Information

Role of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny.

Publications

Role of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny.

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