Inhibition of human cytochromes P450 2A6 and 2A13 by flavonoids, acetylenic thiophenes and sesquiterpene lactones from <i>Pluchea indica</i> and <i>Vernonia cinerea</i>

Abstract

<p>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</b>–<b>4</b> (apigenin, luteolin, chrysoeriol, quercetin) from <i>Vernonia cinerea</i> and <i>Pluchea indica,</i> four hirsutinolide-type sesquiterpene lactones <b>5</b>–<b>8</b> from <i>V. cinerea</i>, and acetylenic thiophenes <b>9</b>–<b>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>_I 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.</p