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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD004445-42
Application #
8434220
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Ilekis, John V
Project Start
1978-09-29
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
42
Fiscal Year
2013
Total Cost
$383,323
Indirect Cost
$181,042
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Hsu, Mei-Hui; Savas, Uzen; Lasker, Jerome M et al. (2011) Genistein, resveratrol, and 5-aminoimidazole-4-carboxamide-1-?-D-ribofuranoside induce cytochrome P450 4F2 expression through an AMP-activated protein kinase-dependent pathway. J Pharmacol Exp Ther 337:125-36
Bumpus, Namandjé N; Johnson, Eric F (2011) 5-Aminoimidazole-4-carboxyamide-ribonucleoside (AICAR)-stimulated hepatic expression of Cyp4a10, Cyp4a14, Cyp4a31, and other peroxisome proliferator-activated receptor ?-responsive mouse genes is AICAR 5'-monophosphate-dependent and AMP-activated protein J Pharmacol Exp Ther 339:886-95
Savas, Uzen; Machemer, Daniel E W; Hsu, Mei-Hui et al. (2009) Opposing roles of peroxisome proliferator-activated receptor alpha and growth hormone in the regulation of CYP4A11 expression in a transgenic mouse model. J Biol Chem 284:16541-52
Hsu, Mei-Hui; Savas, Uzen; Griffin, Keith J et al. (2007) Human cytochrome p450 family 4 enzymes: function, genetic variation and regulation. Drug Metab Rev 39:515-38
Hsu, Mei-Hui; Savas, Uzen; Griffin, Keith J et al. (2007) Regulation of human cytochrome P450 4F2 expression by sterol regulatory element-binding protein and lovastatin. J Biol Chem 282:5225-36
Savas, Uzen; Hsu, Mei-Hui; Griffin, Keith J et al. (2005) Conditional regulation of the human CYP4X1 and CYP4Z1 genes. Arch Biochem Biophys 436:377-85
Savas, Uzen; Hsu, Mei-Hui; Johnson, Eric F (2003) Differential regulation of human CYP4A genes by peroxisome proliferators and dexamethasone. Arch Biochem Biophys 409:212-20
Cowart, L Ashley; Wei, Shouzuo; Hsu, Mei-Hui et al. (2002) The CYP4A isoforms hydroxylate epoxyeicosatrienoic acids to form high affinity peroxisome proliferator-activated receptor ligands. J Biol Chem 277:35105-12
Johnson, Eric F; Hsu, Mei-Hui; Savas, Uzen et al. (2002) Regulation of P450 4A expression by peroxisome proliferator activated receptors. Toxicology 181-182:203-6
Hsu, M H; Savas, U; Griffin, K J et al. (2001) Identification of peroxisome proliferator-responsive human genes by elevated expression of the peroxisome proliferator-activated receptor alpha in HepG2 cells. J Biol Chem 276:27950-8

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