Abstract
The human liver cytochrome P450 (CYP) 2A6 and the respiratory CYP2A13 enzymes play role in nicotine metabolism and activation of tobacco-specific nitrosamine carcinogens. Inhibition of both enzymes could offer a strategy for smoking abstinence and decreased risks of respiratory diseases and lung cancer. In this study, activity-guided isolation identified four flavonoids 1-4 (apigenin, luteolin, chrysoeriol, quercetin) from Vernonia cinerea and Pluchea indica, four hirsutinolide-type sesquiterpene lactones 5-8 from V. cinerea, and acetylenic thiophenes 9-11 from P. indica that inhibited CYP2A6- and CYP2A13-mediated coumarin 7-hydroxylation. Flavonoids were most effective in inhibition against CYP2A6 and CYP2A13, followed by thiophenes, and hirsutinolides. Hirsutinolides and thiophenes exhibited mechanism-based inhibition and in irreversible mode against both enzymes. The inactivation kinetic KI values of hirsutinolides against CYP2A6 and CYP2A13 were 5.32-15.4 and 0.92-8.67 µM, respectively, while those of thiophenes were 0.11-1.01 and 0.67-0.97 µM, respectively.
Keywords:
CYP2A13; CYP2A6; acetylenic thiophenes; flavonoids; sesquiterpene lactones.
MeSH terms
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Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
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Aryl Hydrocarbon Hydroxylases / metabolism
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Asteraceae / chemistry*
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Cytochrome P-450 CYP2A6 / antagonists & inhibitors*
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Cytochrome P-450 CYP2A6 / metabolism
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / isolation & purification
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Enzyme Inhibitors / pharmacology*
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Flavonoids / chemistry
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Flavonoids / isolation & purification
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Flavonoids / pharmacology
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Humans
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Lactones / chemistry
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Lactones / isolation & purification
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Lactones / pharmacology
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Molecular Structure
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Sesquiterpenes / chemistry
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Sesquiterpenes / isolation & purification
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Sesquiterpenes / pharmacology
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Structure-Activity Relationship
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Thiophenes / chemistry
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Thiophenes / isolation & purification
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Thiophenes / pharmacology
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Vernonia / chemistry*
Substances
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Enzyme Inhibitors
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Flavonoids
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Lactones
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Sesquiterpenes
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Thiophenes
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Aryl Hydrocarbon Hydroxylases
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CYP2A13 protein, human
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Cytochrome P-450 CYP2A6
Grants and funding
This work was supported by Thailand Research Fund [grant number TRG 5780056]; Burapha University [grant number 86/2559] and Faculty of Science, Mahidol University [grant number CIF58/025 and CIF59/020].