Anandamide Metabolism by Human Liver and Kidney Microsomal Cytochrome P450 Enzymes to Form Hydroxyeicosatetraenoic and Epoxyeicosatrienoic Acid Ethanolamides

Snider, Natasha T.; Kornilov, A. M.; Kent, Ute M.; Hollenberg, Paul F.

doi:10.1124/jpet.107.119321

Cited by 83 publications

(99 citation statements)

References 37 publications

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“…As reported previously, wild-type CYP3A4 primarily forms four epoxide metabolites of AEA (Snider et al, 2007). Because the 118 residue is near the active site and might be predicted to alter the binding of AEA (Fig.…”

Section: Cyp3a44 Variant Exhibits An Increase In the Formation Of DImentioning

confidence: 80%

“…As shown previously, CYP3A4 metabolizes AEA to form four monoepoxide molecules (Snider et al, 2007(Snider et al, , 2008. These metabolites are 5,6-, 8,9-, 11,12-, and 14,15-EET-EA, and they are formed in a time-and protein concentration-dependent manner.…”

Section: Mutation Of Residue 118 From Leucine To Valine In Human Cyp3a4mentioning

confidence: 94%

“…The monooxygenated product is most likely 19-HETE-EA on the basis of its retention time on the C18 column (Nithipatikom et al, 2001). Wild-type CYP3A4 does not produce this metabolite; however, it has previously been observed as a metabolite of AEA that is formed by human liver microsomes (Snider et al, 2007).…”

Section: Cyp3a44 Variant Exhibits An Increase In the Formation Of DImentioning

confidence: 99%

“…The possibility that the novel monooxygenated product and that the dioxygenated products might be epoxides was then investigated. CYP3A4.4 was incubated with AEA in the presence of added EH (Cayman Chemical) as described previously (Snider et al, 2007). As illustrated in Fig.…”

Section: Cyp3a44 Variant Exhibits An Increase In the Formation Of DImentioning

confidence: 99%

“…It has been found in numerous locations including the brain, plasma, and peripheral tissues. A novel pathway for AEA metabolism by human cytochromes P450 (P450s) has been discovered (Snider et al, 2007). The primary P450 enzyme responsible for the oxidation of AEA in the liver is CYP3A4.…”

Section: Introductionmentioning

confidence: 99%

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Effects of a Commonly Occurring Genetic Polymorphism of Human CYP3A4 (I118V) on the Metabolism of Anandamide

Pratt-Hyatt¹,

Zhang²,

Snider³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The endocannabinoid system plays an important role in numerous physiological processes including mood, appetite, and pain sensation. A critical compound in maintaining cannabinoid tone is the endocannabinoid anandamide (AEA). We have recently shown that AEA is metabolized by several different human cytochromes P450 (P450) to form a number of metabolites, one of which exhibits increased biological activity. CYP3A4, one of the major P450s involved in the metabolism of AEA, produces four major metabolites. One of these metabolites, 5,6-epoxyeicosatrienoic acid ethanolamide (5,6-EET-EA), exhibits a much higher affinity than AEA for the cannabinoid 2 receptor (CB-2), which leads to a marked decrease in intracellular cAMP levels in cells expressing CB-2. There are multiple human alleles of CYP3A4, and the CYP3A4.4 allele has been shown to exhibit a significant decrease in activity.Recombinant CYP3A4*4 was expressed in Escherichia coli and was demonstrated to produce 60% less 6-hydroxytestosterone than the wild-type (WT) 3A4 in a reconstituted system. The metabolism of AEA by the WT and the CYP3A4.4 variant was investigated. The mutant produced 60% less of the four EET-EA metabolites than the WT. The mutant also produced a new peak on liquid chromatography-mass spectrometry not seen with the WT, which corresponded to 19-hydroxyeicosatetraenoic acid-ethanolamide. In addition, the mutant produces four novel peaks at m/z 380, which correspond to the addition of two oxygen atoms, possibly to form a peroxide bond. These data indicate that individuals expressing the CYP3A4.4 allele may exhibit significant variations in the metabolism of AEA as well as any other compounds resembling AEA.

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Section: Cyp3a44 Variant Exhibits An Increase In the Formation Of DImentioning

confidence: 80%

Section: Mutation Of Residue 118 From Leucine To Valine In Human Cyp3a4mentioning

confidence: 94%

Section: Cyp3a44 Variant Exhibits An Increase In the Formation Of DImentioning

confidence: 99%

Section: Cyp3a44 Variant Exhibits An Increase In the Formation Of DImentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of a Commonly Occurring Genetic Polymorphism of Human CYP3A4 (I118V) on the Metabolism of Anandamide

Pratt-Hyatt¹,

Zhang²,

Snider³

et al. 2010

Drug Metab Dispos

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Lipidomic methodologies applicable to the study of endocannabinoids and related compounds: Endocannabinoidomics

Bisogno

Piscitelli

Marzo

2009

Euro J Lipid Sci & Tech

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The identification of the endogenous ligands of the cannabinoid CB 1 and CB 2 receptors (endocannabinoids) as lipids nominally derived from arachidonic acid was a further demonstration that lipid molecules can be endowed with important signaling functions. This discovery was paralleled by the development of ever more sophisticated technologies for the profiling of small molecules, and the subsequent birth and exponential growth of the discipline of "metabolomics" and, in the case of analytical techniques for lipids, of its subdiscipline known as "lipidomics". The application of lipidomics to the analysis of endocannabinoids, and of endocannabinoid-like molecules with activities also at noncannabinoid receptors, is now culminating in the identification of more families of fatty acid derivatives, thus revealing what has been defined as the "endocannabinoid metabolome", and in the development of specific techniques for the lipidomic profiling of these molecules. These new analytical advances are discussed in this article.

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Pharmacological and therapeutic secrets of plant and brain (endo)cannabinoids

Hanŭs

2008

Medicinal Research Reviews

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Research on the chemistry and pharmacology of cannabinoids and endocannabinoids has reached enormous proportions, with approximately 15,000 articles on Cannabis sativa L. and cannabinoids and over 2,000 articles on endocannabinoids. The present review deals with the history of the Cannabis sativa L. plant, its uses, constituent compounds and their biogeneses, and similarity to compounds from Radula spp. In addition, details of the pharmacology of natural cannabinoids, as well as synthetic agonists and antagonists are presented. Finally, details regarding the pioneering isolation of the endocannabinoid anandamide, as well as the pharmacology and potential therapeutic uses of endocannabinoid congeners are presented.

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Anandamide Metabolism by Human Liver and Kidney Microsomal Cytochrome P450 Enzymes to Form Hydroxyeicosatetraenoic and Epoxyeicosatrienoic Acid Ethanolamides

Cited by 83 publications

References 37 publications

Effects of a Commonly Occurring Genetic Polymorphism of Human CYP3A4 (I118V) on the Metabolism of Anandamide

Effects of a Commonly Occurring Genetic Polymorphism of Human CYP3A4 (I118V) on the Metabolism of Anandamide

Lipidomic methodologies applicable to the study of endocannabinoids and related compounds: Endocannabinoidomics

Pharmacological and therapeutic secrets of plant and brain (endo)cannabinoids

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