PERINATAL MECHANISMS OF DETOXIFICATION

Summary

Principal Investigator: Eric F Johnson
Abstract: DESCRIPTION (provided by applicant): Cytochrome P450 (CYP) monooxygenases oxidize a large variety of nutritive and non-nutritive lipids including man-made xenobiotics to reduce toxicity and increase their elimination. The expression of individual P450 enzymes is controlled by a variety of hormonal and metabolic inputs as well as by xenobiotics. The specific aims of this project focus on the regulation and function of human CYP4A11 and CYP4F2, which oxidize both endobiotic and xenobiotic substrates, and contribute to lipid homeostasis, protection from xenobiotics, and signal transduction pathways regulating hemodynamics and inflammation. Although the regulation of CYP4 gene expression has been characterized in various non-human species, significant differences are evident between mammalian species in the number of CYP4 genes and the pathways that govern their expression. The proposed studies address mechanisms of human CYP4F2 gene regulation through the identification of cis-acting control elements and the associated transcription factors that regulate expression of CYP4F2 in response to xenobiotics, hormones and nutritional status. The current proposal focuses on the role of the AMP activated protein kinase and sterol regulatory element binding proteins in this process. CYP4F2 transgenic mice will be generated and used together with CYP4A11 transgenic mice to characterize regulatory responses to xenobiotics and to physiologic alterations that accompany conditions such as nutritional status and inflammation. The CYP4A11 and CYP4F2 transgenes will be expressed in Cyp4a10 null mice to gauge the effect of expression of each transgene on the susceptibility of the Cyp4a10 null mice to develop salt-sensitive hypertension and to relate these changes to differences in renal and hepatic lipid metabolism, inflammation and gene expression. The underlying mechanisms are likely to contribute to the reported association of genetic variation of the human CYP4A11 and CYP4F2 genes with risks for hypertension and related vascular disorders. These mechanisms are likely to reflect the roles of Cyp4a10, CYP4A11 and CYP4F2 in lipid metabolism with consequent effects on gene regulation that contribute to salt dependent hypertension in mice. PUBLIC HEALTH RELEVANCE: The proposed studies will characterize regulatory pathways that enhance or diminish the body's capacity to metabolize and to eliminate potentially toxic excess amounts of nutrients or foreign chemicals in response to xenobiotics, diet and endocrine status. Additionally, we will address how genetic deficiencies of this capacity affect susceptibility to hypertension due to renal and liver dysfunction.
Funding Period: 1978-09-29 - 2016-01-31
more information: NIH RePORT

Top Publications

  1. ncbi Regulation of human cytochrome P450 4F2 expression by sterol regulatory element-binding protein and lovastatin
    Mei Hui Hsu
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 282:5225-36. 2007
  2. ncbi Human cytochrome p450 family 4 enzymes: function, genetic variation and regulation
    Mei Hui Hsu
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    Drug Metab Rev 39:515-38. 2007
  3. pmc Opposing roles of peroxisome proliferator-activated receptor alpha and growth hormone in the regulation of CYP4A11 expression in a transgenic mouse model
    Uzen Savas
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 284:16541-52. 2009
  4. pmc Genistein, resveratrol, and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside induce cytochrome P450 4F2 expression through an AMP-activated protein kinase-dependent pathway
    Mei Hui Hsu
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    J Pharmacol Exp Ther 337:125-36. 2011
  5. pmc 5-Aminoimidazole-4-carboxyamide-ribonucleoside (AICAR)-stimulated hepatic expression of Cyp4a10, Cyp4a14, Cyp4a31, and other peroxisome proliferator-activated receptor α-responsive mouse genes is AICAR 5'-monophosphate-dependent and AMP-activated protein
    Namandjé N Bumpus
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, MEM 255, La Jolla, CA 92037, USA
    J Pharmacol Exp Ther 339:886-95. 2011

Research Grants

Detail Information

Publications5

  1. ncbi Regulation of human cytochrome P450 4F2 expression by sterol regulatory element-binding protein and lovastatin
    Mei Hui Hsu
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 282:5225-36. 2007
    ..Collectively, these results demonstrate that SREBPs transactivate CYP4F2 transcription and that CYP4F2 induction by statins is mediated by SREBP-2...
  2. ncbi Human cytochrome p450 family 4 enzymes: function, genetic variation and regulation
    Mei Hui Hsu
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    Drug Metab Rev 39:515-38. 2007
    ..Comparative differences between the human and rodent CYP4 enzymes regarding catalytic function and conditional expression are also discussed...
  3. pmc Opposing roles of peroxisome proliferator-activated receptor alpha and growth hormone in the regulation of CYP4A11 expression in a transgenic mouse model
    Uzen Savas
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 284:16541-52. 2009
    ..In contrast, increased exposure to growth hormone down-regulates CYP4A11 expression in liver...
  4. pmc Genistein, resveratrol, and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside induce cytochrome P450 4F2 expression through an AMP-activated protein kinase-dependent pathway
    Mei Hui Hsu
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    J Pharmacol Exp Ther 337:125-36. 2011
    ..These results suggest that activation of AMPK by cellular stress and endocrine or pharmacologic stimulation is likely to activate CYP4F2 gene expression...
  5. pmc 5-Aminoimidazole-4-carboxyamide-ribonucleoside (AICAR)-stimulated hepatic expression of Cyp4a10, Cyp4a14, Cyp4a31, and other peroxisome proliferator-activated receptor α-responsive mouse genes is AICAR 5'-monophosphate-dependent and AMP-activated protein
    Namandjé N Bumpus
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, MEM 255, La Jolla, CA 92037, USA
    J Pharmacol Exp Ther 339:886-95. 2011
    ..These results suggest that PPARα is activated by increased concentrations of free fatty acids that may arise from impaired fatty acid metabolism caused by altered levels of ATP, AMP, and ZMP after AICAR or adenosine treatment...

Research Grants30

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  2. A Novel Cellular Mechanism for Reducing Hyperlipidemia
    Jingwen Liu; Fiscal Year: 2013
    ....
  3. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  4. Hypo-Lipidemic Actions of Creosote Bush-Derived NDGA
    Salman Azhar; Fiscal Year: 2013
    ....
  5. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..