Research Highlight: Understanding Individual Differences in Chemical and Drug Metabolism

Environmental exposures affect health. 
Exposure science is the study of chemical, physical, or biological agents that humans come in contact with in their environments. Exposure information is needed to understand health risks from chemicals and other agents.

Evaluating the amount of specific chemicals people are exposed to allows scientists to estimate the dose of the chemicals people are getting. Knowing this allows researchers to develop studies to test whether that dose may affect human health. Results from exposure science studies are critical for developing interventions to prevent or minimize health hazards.

As our Center theme is gene-environment interactions, measuring exposures and understanding the dose is needed to be able to estimate the interaction of genes with chemical exposures.

Exposure science is known for its interdisciplinary approach. The Exposure Sciences ARE draws on the expertise of Exposure Sciences Program faculty within our department, Environmental and Occupational Health Sciences, including two faculty whose main appointments are in Environmental Engineering and Biostatistics. Two more Exposure Sciences ARE faculty come from the School of Pharmacy.

The Exposure Sciences ARE members work collaboratively with colleagues in the other CEEH cores to provide state-of-the-art methods in the use of various exposure assessment tools including biomarkers, a molecule in blood or urine that indicates a physiological or a particular disease state.

Exposure Sciences ARE member Yvonne Lin, a faculty in the School of Pharmacy, led a study this year to search for a biomarker in urine that would reflect the activity of a metabolic enzyme called cytochrome P450 2D6 (CYP2D6). This enzyme plays a role in metabolizing 15% of clinical drugs, including antipsychotics, antidepressants, beta-blockers, opioid analgesics, and dextromethorphan, a cough suppressant found in many over-the-counter cough and cold medicines.

CYP2D6 has wide genetic diversity. Some healthy people have no CYP2D6 activity (these folks are called Poor Metabolizers), while others have some activity and still others have extensive activity.
Phenotyping to test a person’s level of CYP2D6 activity is done with probe drugs or drug cocktails and blood draws. A safer, less invasive method would be to identify a biomarker, for example in urine, to measure the real-time activity of the CYP2D6 enzyme. This is what Lin and her team members did.

Child participants were given cough syrup.
One hundred healthy children were given the drug dextromethorphan, a common over-the-counter medication given to adults and children. Urine samples were collected before and after participants were given the drug. Samples were analyzed to try to identify urinary metabolites, small molecule fragments of the drug that could predict the child’s CYP2D6 phenotype.

Lin and her team were able to identify a candidate biomarker molecule that indicated the metabolism of dextromethorphan. The molecule was nearly absent in the 9 poor metabolizers and present in 91 participants in proportion to their CYP2D6 phenotype.

The team searched established databases to identify the molecule, but found no matches. They identified the biomarker by its mass, 443.3026 Da, and refer to it as Unknown 1, or Unk1. A paper about the study has been submitted and is currently in review.

Next steps are to identify Unk1 and validate it as a biomarker that can be used to measure clinical drug metabolism. This discovery has the potential to improve personalized medicine in children by providing a means to measure in a urine sample an individual ‘s response to the clinical drugs metabolized by CYP2D6.

Dr. Lin’s research interests include pharmacokinetics, the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body; pharmacogenetics, genetic differences in metabolism that can affect individual responses to drugs; the regulation of drug metabolizing enzymes such as CYP2D6 in children; the effect of obesity and diabetes on the metabolism and elimination of clinical drugs, and metabolomics, the study of the chemical fingerprints and metabolites left behind in metabolism, as a tool to identify biomarkers.

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