Variation in neurotransmitter transporters, receptors and abnormal levels of neurotransmitters potentially are involved in neurological diseases including schizophrenia, bipolar affective disorder, autism, affective disorder, late onset Alzheimer's disease, Parkinson's disease and others. Fundamental information characterizing human neurotransmitter metabolism associated with neurodegenerative diseases could provide new approaches to understanding the pathology and developing new therapeutics. Our central hypothesis is that lack of detoxication of endogenous or xenobiotic amines underlies the pathological condition of some CNS diseases. The human flavin-containing monooxygenase (FMO) is one of the major human enzyme systems that contribute to the detoxication of endogenous, environmental and dietary nitrogen-containing substances. The overall goal of our work is to understand the details of FMO-mediated N-oxygenation of amines and hydroxylamines. Accumulation of hydroxylamines in the CNS may lead to cytotoxicity or apoptosis. To test this, fundamental information about human brain FMO N-oxygenation is required. The overall goal will be accomplished by addressing five Specific Aims including:
Aim 1 : cDNA-express the major forms of human brain FMO;
Aim 2 : Chemically synthesize amine metabolites of human brain FMO;
Aim 3 : Determine the kinetics and mechanism of human brain FMO amine N-oxygenation;
Aim 4 : Test the effects of human brain FMO amine metabolites on neuronal cell function including cytotoxicity and apoptosis, and Aim 5: Investigate the mechanism of amine metabolites on human neurotransmitter function. The significance is that fundamental biochemical information will result in new insight about the way endogenous and xenobiotic and dietary amines are metabolized in human brain. Such fundamental information will be useful in the development of safer drugs, the prevention of adverse drug reactions and the protection of humans from disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059618-03
Application #
6722773
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
May, Michael K
Project Start
2002-04-15
Project End
2006-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
3
Fiscal Year
2004
Total Cost
$374,447
Indirect Cost
Name
Human Biomolecular Research Institute
Department
Type
DUNS #
030864867
City
San Diego
State
CA
Country
United States
Zip Code
92121
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Motika, Meike S; Zhang, Jun; Zheng, Xueying et al. (2009) Novel variants of the human flavin-containing monooxygenase 3 (FMO3) gene associated with trimethylaminuria. Mol Genet Metab 97:128-35
Zhang, Jun; Chaluvadi, Madhusudana R; Reddy, Rob et al. (2009) Hepatic flavin-containing monooxygenase gene regulation in different mouse inflammation models. Drug Metab Dispos 37:462-8
Cashman, John R (2008) Role of flavin-containing monooxgenase in drug development. Expert Opin Drug Metab Toxicol 4:1507-21
Cashman, John R; Zhang, Jun; Nelson, Matthew R et al. (2008) Analysis of flavin-containing monooxygenase 3 genotype data in populations administered the anti-schizophrenia agent olanzapine. Drug Metab Lett 2:100-14
Motika, Meike S; Zhang, Jun; Cashman, John R (2007) Flavin-containing monooxygenase 3 and human disease. Expert Opin Drug Metab Toxicol 3:831-45
Zhang, Jun; Cerny, Matt A; Lawson, Matt et al. (2007) Functional activity of the mouse flavin-containing monooxygenase forms 1, 3, and 5. J Biochem Mol Toxicol 21:206-15
Yamazaki, Hiroshi; Fujita, Haruka; Gunji, Takaaki et al. (2007) Stop codon mutations in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population. Mol Genet Metab 90:58-63
Shimizu, Makiko; Yano, Hiroshi; Nagashima, Satomi et al. (2007) Effect of genetic variants of the human flavin-containing monooxygenase 3 on N- and S-oxygenation activities. Drug Metab Dispos 35:328-30
Shimizu, Makiko; Cashman, John R; Yamazaki, Hiroshi (2007) Transient trimethylaminuria related to menstruation. BMC Med Genet 8:2

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