You are here:
Constructing an Enzyme Ontogeny Database to Improve Characterization of Toxicokinetic Lifestage Differences
Citation:
Rowan, E., R. Hines, Suryanarayana Vulimiri, B. Wetmore, C. Brinkerhoff, A. Jarabek, D. Kapraun, E. Kenyon, C. Ring, J. Wambaugh, AND R. Sayre. Constructing an Enzyme Ontogeny Database to Improve Characterization of Toxicokinetic Lifestage Differences. NC Symposium on Life/Data Sciences, Precision Medicine/Environmental Health, RTP, NC, May 08, 2023. https://doi.org/10.23645/epacomptox.22266274
Impact/Purpose:
Our new database supports comparison of values of activity of xenobiotic metabolizing agents on the tissue level, plasma binding protein and membrane transport protein ontogeny, and life stage related changes in key organ system mass and function across sources, addressing the need for more enzyme and TK data across early life stages, and allowing the identification of data gaps to highlight avenues for future research.
Description:
Certain enzymes aid in the metabolism and elimination of specific substrates – including drugs and toxicants – from the body. Across different life stages, the availability of specific enzymes varies, which greatly impacts the efficiency at which the body can eliminate parent compounds and their metabolites. The enzymes active at different life stages may also lead to differential metabolic activation of a parent compound, resulting in life-stage-dependent differences in toxic metabolites. Thus, knowledge of the presence, capacity, and activation of specific enzymes at different life stages can help expand understanding and modeling capacity of the toxicokinetic (TK) differences between infants, children, and adults. In addition to differences in enzymatic expression during early life, the size of different body compartments and circulatory flows between them are rapidly changing, which also affects not only the metabolism of compounds but their distribution. To create a greater web of knowledge surrounding TK life-stage differences, we present a workflow to create a publicly available database containing enzyme and transporter data for early life stages. We sourced data by identifying multiple enzyme-focused data sources and harmonized the data in our database via normalization to a set of fields common across all data sources and interoperable with external datasets. We then utilized machine learning methods to identify similar papers to further populate the database from the open literature. Our literature search focused on the activity of xenobiotic metabolizing agents on the tissue level, plasma binding protein and membrane transport protein ontogeny, and life stage related changes in key organ system mass and function. Both human and rodent species data were captured to encourage investigation of case suitability for cross-species extrapolation. All data records are stored in a MySQL data model along with their curated metadata. The database currently includes data on over 50 enzymes in mice, rats, and humans with a collection focus on data from early in each species’ life for comparison to values in adults. We also describe data quality evaluations for this resource and define quality flags that indicate each value’s potential to inform risk assessment. Our database supports comparison of values across sources, addresses the need for more enzyme and TK data across early life stages, and allows the identification of data gaps to highlight avenues for future research. Additionally, these data can be used as inputs to PBPK (physiologically based pharmacokinetics) models designed to estimate internal doses of toxicants in infants and children, two sensitive life-stages. This knowledge is valuable for human health safety evaluations.
URLs/Downloads:
DOI: Constructing an Enzyme Ontogeny Database to Improve Characterization of Toxicokinetic Lifestage Differences
POSTER.PDF (PDF, NA pp, 576.232 KB, about PDF)