Influence of genetic polymorphisms and epigenetic alterations in cytochrome P450, cytochrome P450 oxidoreductase (POR), glucuronosyltransferase (UGT), and nuclear receptor genes on drug metabolism.
Xiaobo Zhong, Ph.D., received his postdoctoral training in human genomics and population genetics in the Department of Human Genetics at Yale University School of Medicine. He began as Assistant Professor of Pharmacology and Toxicology at KUMC in July 2004.
Dr. Zhong’s research interests mainly focus on pharmacogenomics, pharmacoepigenomics, and personalized medicines. His long-term research goals are to better understand how genetic polymorphisms and epigenetic alterations result in varied responses to drugs. Presently, he is proposing research to systematically examine genetic polymorphisms and epigenetic alterations (DNA methylation, histone modifications, and chromatin dynamic alterations) in the genes involved in drug elimination pathways ADME (drug absorption, distribution, metabolism and excretion). Dr. Zhong’s studies focus on what genetic polymorphisms and epigenetic alterations in which genes contribute to the differences of metabolic rates in different patients.
His recent NIH funded project is a research project in a program project of “Centers of Biomedical Research Excellence (COBRE)” which focuses on “Nuclear Receptors in Liver Health and Disease”. His project focuses on “identification and functional characterization of genetic polymorphisms in nuclear receptor genes of pregnane X receptor (PXR), constitutive active receptor (CAR), and retinoid x receptor (RXR)”. PXR/RXA and CAR/RXR heterodimers control transcription of several cytochrome P450, glucuronosyltransferase, and membrane transporter genes and acts as a “sensor” to control drug metabolism. Identification of genetic polymorphisms in the PXR, CAR, and RXR genes may explain inter-individual differences of drug metabolic rates.
His PhRMA Foundation Research Grant focuses on identification of genetic polymorphisms in cytochrome P450 oxidoreductase gene and their influence on P450-catalyzed drug metabolism and detoxification.
Dr. Zhong’s other projects focus on translational research. His laboratory has developed a simple, inexpensive, and high-throughput platform using thin-film biosensor chip which can simultaneously genotype SNPs, tow-adjacent SNPs, small deletion/insertion and microsatellite repeat polymorphisms. Using this platform, his team is developing pharmacogenomics tests recommended by FDA for warfarin (anticoagulation drug), irinotecan (chemotherapy agent for colon cancer), gefitinib and erlotinib (chemotherapy drugs for lung cancer), and thiopurine drugs (chemotherapy agents for acute lymphoblastic leukemia). Future goal is to establish a pharmacogenomics clinical laboratory in the department to provide clinical services for hospitals in the heartland states.
Selected Publications
Hart SN and Zhong XB. P450 oxidoreductase: genetic polymorphisms and implications to drug metabolism and toxicity (invited review). Expert Opinion on Drug Metabolism and Toxicology, 4(4):1-14, 2008.
Hart SN, Wang S, Nakamoto K, Wesselman C, Li Y, and Zhong XB. Genetic polymorphisms in cytochrome P450 oxidoreductase influence microsomal P450-catelyzed drug metabolism. Pharmacogenetics and Genomics, 18(1):11-24, 2008.
Li Y, Wesselman C, Hart SN, Nakamoto K, and Zhong XB. Development of a pharmacogenetic test for predicting irinotecan severe toxicity in colorectal cancer chemotherapy. Submitted.
Hart SN, Li Y, Nakamoto K, Wesselman C, and Zhong XB. Novel SNPs in cytochrome P450 oxidoreductase. Drug Metabolism and Pharmacokinetics, 22(4):322-326, 2007.
Nakamoto K, Kidd JR, Jenison RD, Klaassen CD, Wan YJ, Kidd KK, and Zhong XB. Genotyping and haplotyping of CYP2C19 functional alleles on thin-film biosensor chips. Pharmacogenetics and Genomics, 17(2):103-114, 2007.
Bai SL, Zhong XB, Ma LG, Zheng WJ, Fan LM, Wei N, and Deng XW. A simple and reliable assay for detecting specific nucleotide sequence variations in plants using optical thin-film biosensor chips. The Plant Journal, 49:354-366, 2007.
Nakamoto K, Wang S, Jenison RD, Guo GL, Klaassen CD, Wan YJ, and Zhong XB. Linkage disequilibrium blocks, haplotype structure, and htSNPs of human CYP7A1 gene. BMC Genetics, 7:29-37, 2006.
Zhong, XB., Leng, L., Beitin, A., Chen, R., McDonald, C., Hsiao, B.,Jenison, R. D., Kang, I., Park, S.-H., Lee, A., Gregersen, P., Thuma, P., Bray-Ward, P., Ward, D. C., Bucala, R.. Simultaneous detection of microsatellite repeats and SNPs in the macrophage migration inhibitory factor (MIF) gene by thin-film biosensor chips and application to rural field studies. Nucleic Acids Res. 33 (13): e121, 2005.
Zhong XB, Reynolds R, Kidd JR, Kidd KK, Jenison R, Marlar RA, Ward DC. Single-nucleotide polymorphism genotyping on optical thin-film biosensor chips. Proc Natl Acad Sci U S A. 100(20):11559-1564, 2003.
Zhong XB, Lizardi PM, Huang XH, Bray-Ward PL, Ward DC. Visualization of oligonucleotide probes and point mutations in interphase nuclei and DNA fibers using rolling circle DNA amplification. Proc Natl Acad Sci U S A. 98(7):3940-3945, 2001.
Grichtchenko II, Choi I, Zhong XB, Bray-Ward P, Russell JM, Boron WF. Cloning, characterization, and chromosomal mapping of a human electroneutral Na+-driven Cl-HCO3 exchanger. J Biol Chem. 276(11): 8358-8363, 2001.
Contact Information
Xiaobo Zhong, PhD
Assistant Professor
Department of Pharmacology, Toxicology and Therapeutics
The University of Kansas Medical Center
MS 1018
3901 Rainbow Boulevard
Kansas City, Kansas 66160
Phone: (913) 588-0401
Fax: (913) 588-7501
Email: xzhong@kumc.edu
Updated 03/11/08
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The University of Kansas Medical Center