Journal
PROSTAGLANDINS & OTHER LIPID MEDIATORS
Volume 88, Issue 1-2, Pages 10-17Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.prostaglandins.2008.08.004
Keywords
Lipid signaling; Mass spectrometry; Cytochrome P450; N-Arachidonoyl dopamine; Cannabinoid; Vanilloid; Liver microsomes; TRPV1; Hydroxylated metabolites
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Funding
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA018224, F32DA016825] Funding Source: NIH RePORTER
- NIDA NIH HHS [F32 DA016825, F32 DA016825-03, R01 DA018224, R01 DA018224-04] Funding Source: Medline
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N-Arachiclonoyl dopamine (NADA) is an endogenous lipid that modulates signal transduction in neuronal and immune pathways. NADA activates the non-selective cation channel, transient receptor potential vanilloid type 1 (TRPV1) and cannabincrid receptor 1. That NADA is comprised of an arachidonic acid (AA) backbone suggests that it may be metabolized through many of the enzymes that act upon AA such as the other AA-derived signaling lipids. the endogenous cannabinoids. To investigate the metabolism of NADA through the cytochrome P450 (CYP450) metabolic pathway, we studied the in vitro rat liver microsomal production of hydroxylated metabolites and their activity at recombinant human TRPV1 receptors. We showed that following microsomal activation in the presence of NADA. omega and (omega-1) hydroxylated metabolites (19- and 20-HETE-DA) were formed. These metabolites were active at recombinant human TRPV1 receptors, inducing a dose-dependent calcium influx. Both metabolites exhibited lower potency compared to NADA. We conclude that CYP450 enzymes are capable of metabolizing this signaling lipid forming a larger family of potential neuromodulators. (C) 2008 Elsevier Inc. All rights reserved.
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