Inhibition of human cytochromes P450 2A6 and 2A13 by flavonoids, acetylenic thiophenes and sesquiterpene lactones from Pluchea indica and Vernonia cinerea
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 <b>1-4</b>
(apigenin, luteolin, chrysoeriol, quercetin) from <i>Vernonia cinerea</i> and <i>Pluchea
indica, </i>four hirsutinolide-type sesquiterpene lactones <b>5-8</b> from <i>V.
cinerea</i>, and acetylenic thiophenes <b>9-11</b> from <i>P. indica</i> 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 <i>K</i><sub>I</sub> 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
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