When she became interested in performing research, Emily Grossman contacted Professor Blumberg, who put her under the guidance of Dr. Matthew Milnes, a postdoctoral researcher in his lab. Emily’s work focuses on a nuclear hormone receptor that is vital in de-toxifying the body and is responsible for the regulation of the metabolism of over 60% of currently used pharmaceutical drugs. She has enjoyed working with the people in her lab and learning new techniques and protocols. Completing projects on her own has increased her confidence in her abilities. Emily will move on to graduate school in September 2007.

Homeostasis in the body is maintained through many mechanisms. The steroid and xenobiotic receptor (SXR) is a nuclear hormone receptor that regulates catabolic enzymes responsible for the metabolism of over 60% of currently used drugs. Individuals show considerable differences in their ability to metabolize drugs; one hypothesis is that single nucleotide polymorphisms in this receptor are responsible for some of this variability. In this study, we tested the ability of the SXR harboring single nucleotide polymorphisms to respond to known activators. We recreated 14 known single nucleotide polymorphisms within this receptor, and tested these mutant receptors in a cell-based assay system using a luciferase reporter for responsiveness to three known ligands. Compared with the activity of the wild type receptor, we found that most of the polymorphisms had little or no effect on the ability of this receptor to respond to the ligands. However, D163G and A370T had profound effects, differing from wild type by over 77%. Considering that SXR plays such a central role in drug metabolism, the frequency of these polymorphisms in the population has important implications for drug development and potential drug-drug interactions.

Bruce Blumberg School of Biological Sciences

There are striking differences in individuals’ abilities to detoxify and metabolize pharmaceuticals, bioactive dietary compounds, and xenobiotic chemicals. Understanding these differences is critical for identifying individualized treatments and in assessing the real risks posed by exposure to dietary or xenobiotic chemicals. The steroid and xenobiotic receptor, SXR, is the primary regulator of enzymes that lead to the metabolism of drugs and chemicals. Emily’s research tested the effects of variations in the SXR sequence on the ability of SXR to respond to a panel of xenobiotic chemicals. She found significant differences in the ability of SXR to activate gene expression in response to chemical exposure, and that the effects were specific to the tested chemical. These results have broad implications in understanding human response to drugs and chemicals.