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.
Footnotes
- Received January 5, 2016.
- Accepted February 25, 2016.
↵1 Current affiliation: Milwaukee, Wisconsin.
↵2 Current affiliation: Department of Pediatrics Critical Care, University of Michigan Health System, Ann Arbor, Michigan.
↵3 Cary, North Carolina.
↵4 Samsara Sciences, San Diego, California.
↵5 Department of Laboratory Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden.
↵6 U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, North Carolina
This work was supported in part by the National Institutes of Health [Grant GM081344] (R.N.H. and D.G.M.) and the Swedish Research Council, Ventenskaprådet and the Torsten och Ragnar Söderberg Stiftelse (R.G. and S.C.S.).
↵This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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