I am a pursuing a Ph.D. in Toxicology at KU Medical Center. I received my B.S. (2006) pioneering a new Biotechnology program at Missouri Western State University, which provided training in biology, chemistry, and business.
Research Interests
Pediatric adverse drug reactions (ADRs) from properly prescribed medications pose a clinically significant problem since ~31,000 children each year are hospitalized as a result of life threatening ADRs. Infants and young children are at a greater risk than adults for developing liver toxicity from certain drugs (e.g. cisapride), but less susceptible for others (e.g. acetaminophen). These variations in drug response between children and adults are manifested through differences in clearance of drugs by drug metabolizing enzymes. Importantly, members of the Cytochrome P450 (CYP) 2D and 3A families are the primary clearance mechanisms for over 60% of commonly prescribed drugs. Although both adult and pediatric livers contain the same set of CYP2D and CYP3A genes, the expression levels of individual drug metabolizing enzymes vary with age. Defining ontogenic expression patterns of drug metabolizing enzyme genes, and more importantly the mechanisms governing their control, could lead to novel therapies or dosing strategies based on pediatric physiology, rather than the current method of overly simplistic body weight or surface area calculations. Furthermore, much data have been generated to show that developmentally programmed gene expression patterns are associated with dynamic epigenetic modifications, including DNA and histone methylation. However, little focus has been directed toward understanding the epigenetic relationship between the developing liver and ontogenic expression of drug metabolizing enzymes to explain pediatric toxicity. Therefore, our lab studies the dynamic epigenetic environment of the developing liver to tease out the mechanisms facilitating ontogenic gene expression frequently observed in postnatal development.
I have also studied pharmacogenomics, which uses DNA as a predictive biomarker for determining how well a patient will respond to prescription drugs. Recently our lab has identified a mutation in P450 reductase (POR) that closely associates with decreased metabolism for 8 of 10 major dug metabolizing enzymes. Although many others have found mutations in the cytochrome P450 superfamily of enzymes (the primary mechanism by which drugs get metabolized by the body) which affect the rate of metabolism and thus leading to bioaccumulation and toxicity, those mutations can only explain how one of many P450s interacts with one substrate or class of substrates. POR, however, is essential to activate most of the P450s, so the idea is that a mutation in POR will have consequences on all drugs metabolized by the P450 system.
Finally, I am a 2007-2011 Self Graduate Fellow from the University of Kansas, which not only supports my stipend and tuition expenses, but also includes a development program to provide additional training in communication, management, and leadership. More information on the Self Fellowship can be found at http://www2.ku.edu/~selfpro/.
Publications
Hart SN, Zhong XB. P450 oxidoreductase: genetic polymorphisms and implications for drug metabolism and toxicity. Expert Opin Drug Metab Toxicol. 2008 Apr;4(4):439-52. Review. PMID: 18433346
Hart SN, Wang S, Nakamoto K, Wesselman C, Li Y, Zhong XB. Genetic polymorphisms in cytochrome P450 oxidoreductase influence microsomal P450-catalyzed drug metabolism. Pharmacogenet Genomics. 2008 Jan;18(1):11-24. PMID: 18216718 [PubMed - indexed for MEDLINE]
Eckdahl TT, Brown AD, Hart SN, Malloy KJ, Shott M, Yiu G, Hoopes LL, Heyer LJ. Microarray analysis of the in vivo sequence preferences of a minor groove binding drug. BMC Genomics. 2008 Jan 23;9:32. PMID: 18215295
Hart SN, Li Y, Nakamoto K, Wesselman C, Zhong XB. Novel SNPs in cytochrome P450 oxidoreductase. Drug Metab Pharmacokinet. 2007 Aug;22(4):322-6. PMID: 17827787
Contact Information
Updated 9/5/08
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