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Human Metabolism Group

P450: Regulation and Polymorphisms

Joyce A. Goldstein, Ph.D.
Joyce A. Goldstein, Ph.D.
Principal Investigator

Tel (919) 541-4495
Fax (919) 541-3647
P.O. Box 12233
Mail Drop A3-02
Research Triangle Park, North Carolina 27709
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Research Summary

The Human Metabolism Group studies function, transcriptional regulation and genetic polymorphisms of the human cytochrome P450 enzymes (CYPs) which metabolize foreign compounds such as clinically-used drugs, herbal medicines, and environmental chemicals. Our group has focused on the CYP2C subfamily which includes four members: CYP2C8, CYP2C9, CYP2C18 and CYP2C19. These enzymes metabolize approximately 20% of clinically known drugs as well as over-the-counter remedies such as ibuprofen and the antiulcer drug omeprazole. The CYP2C enzymes also metabolize endogenous compounds such as and retinoic acid and metabolize arachidonic acid to biologically active intermediates. CYP2C enzymes also metabolize environmental compounds such as pesticides and herbicides.

Polymorphisms in the genes for CYP enzymes lead to inter-individual variability in the ability of humans to metabolize drugs and environmental chemicals. Polymorphisms affect the half-life, efficacy and toxicity of clinically-used drugs and can potentially affect susceptibility to environmentally-caused disease states such as cancer. Identification of genetic defects and development of genetic tests which identify polymorphisms are a prerequisite to identifying whether certain individuals are at high risk to adverse effects of clinically used drugs and other xenobiotics. Identifying polymorphisms in CYP enzymes is now used to determine mines risks of new drugs to susceptible individuals in clinical trials, and also holds promise for individualized medicine in the future.

The group studies how the CYP2C genes and proteins are regulated both constitutively in hepatic and extrahepatic tissues, and how foreign compounds such as rifampicin, phenobarbital, herbal medicines, glucocorticoids and environmental compounds upregulate expression of these enzymes. This up regulation is a source of drug-drug interactions, and adverse drug reactions, one of the leading causes of death in humans. We examine the molecular mechanism of these changes, analyzing promoter activity by a variety of techniques, identifying receptors such as the constitutive androstane receptor (CAR), the pregnane X receptor ( PXR), hepatic nuclear factor 4α(HNF4 and co-regulators which modulate interaction of these receptors with DNA, studying both protein-protein and protein-DNA interactions.

Major areas of research:

  • The function, transcriptional regulation and genetic polymorphisms of CYPs
  • The constitutive regulation of CYP2C genes and proteins in hepatic and extrahepatic tissues

Current projects:

  • Functional assessment of human and murine CYP2Cs and their ability to metabolize clinical drugs, herbal medicines, environmental compounds and endogenous compounds
  • Discovery and functional assessment of polymorphisms in the human CYPs in recombinant studies and in clinical studies.
  • Prospective studies of influence of CYPC9 polymorphisms: e.g., the risk of adverse drug reactions to warfarin and other drugs
  • The transcriptional up-regulation of the CYP2C subfamily by nuclear orphan receptors such as the constitutive androgen receptor (CAR), the pregnane X receptor (PXR), hepatic nuclear factor 4α, and other nuclear receptors which also lead to inter-individual variability and drug-drug interactions
  • Identifying co-regulators and co-repressors which are involved in protein-protein and protein-DNA interactions thus modulating regulation of CYP2C enzymes
  • Regulation of CYP enzymes constitutively and in response to physiological stress and disease in both liver and extrahepatic tissues

Joyce A. Goldstein, Ph.D., heads the Human Metabolism Group within the Laboratory of Pharmacology. She received her Ph.D. in pharmacology from the University of Texas Southwestern Medical School, at Dallas, Texas in 1968. She holds two patents on the discovery of CYP2C19 and the major polymorphism in this enzyme, and has published over 132 peer-reviewed articles in leading biomedical journals, as well as 24 book chapters. She is a member of the Faculty of 1000, an ISI Highly Cited Author in Pharmacology (2006) and is Board Certified by the American Board of Toxicology. She was the Acting Chief of the Biochemistry Branch at EPA, Research Triangle Park, North Carolina before joining NIEHS in 1977.

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Last Reviewed: November 30, 2007