Metabolism of the major Echinacea alkylamide N-isobutyldodeca-2E,4E,8Z,10Z-tetraenamide by human recombinant cytochrome P450 enzymes and human liver microsomes.
Echinacea preparations are used for the treatment and prevention of upper respiratory tract infections. The phytochemicals believed responsible for the immunomodulatory properties are the alkylamides found in ethanolic extracts, with one of the most abundant being the N-isobutyldodeca-2E,4E,8Z,10Z-tetraenamide (1). In this study, we evaluated the human cytochrome P450 enzymes involved in the metabolism of this alkylamide using recombinant P450s, human liver microsomes and pure synthetic compound. Epoxidation, N-dealkylation and hydroxylation products were detected, with different relative amounts produced by recombinant P450s and microsomes. The major forms showing activity toward the metabolism of 1 were CYP1A1, CYP1A2 (both producing the same epoxide and N-dealkylation product), CYP2A13 (producing two epoxides), and CYP2D6 (producing two epoxides and an hydroxylated metabolite). Several other forms showed less activity. In incubations with human liver microsomes and selective inhibitors, CYP2E1 was found to be principally responsible for producing the dominant, hydroxylation product, whereas CYP2C9 was the principal source of the epoxides and CYP1A2 was responsible for the dealkylation product. In summary, in this study the relative impacts of the main human xenobiotic-metabolizing cytochrome P450s on the metabolism of a major Echinacea alkylamide have been established and the metabolites formed have been identified.
Toselli
F
F
School of Biomedical Sciences, University of Queensland, St Lucia, Australia.
Matthias
A
A
Bone
K M
KM
Gillam
E M J
EM
Lehmann
R P
RP
D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D020900:Echinacea / Q000737:chemistry*; D004852:Epoxy Compounds / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000378:metabolism*; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
D004852:Epoxy Compounds; C552244:N-isobutyldodeca-2E,4E,8Z,10Z-tetraenamide; D053284:Polyunsaturated Alkamides; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System