Inhibition of Human CYP1A1/A2 by a Hydroalcoholic Extract and Its Neolignan Constituents from Piper rivinoides

Lignans and neolignans, commonly found in plants, are generally composed of two phenylpropane (C₆-C₃) units with a marked diversity of molecular structures and biological activities of therapeutic interest. They serve as lead compound for organic synthesis of derivatives intended to optimize the pharmacological activity, and, also, for studying structure-activity relationships. Piperaceae species are one of the richest natural sources of lignans and neolignans. In the leaves of Piper rivinoides Kunth, Piperaceae, some biologically active neolignans with leishmanicidal, antibacterial, and antitumor effects have been identified. Furthermore, it had been shown that the neolignans conocarpan, eupomatenoid-5, and eupomatenoid-6, isolated from P. rivinoides leaves inhibited CYP1A1/2 activity in the rat liver microsomes. The present study extends these observations and finds that the crude hydroalcoholic extract of P. rivinoides leaves (100 µg/ml) and conocarpan, eupomatenoid-5, and eupomatenoid-6 (100 µM) inhibited the 7-ethoxyresorufin-O-deethylase and 7-methoxyresorufin-O-demethylation activities catalyzed by the cytochrome P450 isoforms rhCYP1A1 and rhCYP1A2. Molecular docking analysis has suggested that π-π stacking interactions involving residues Phe123, Phe224, and Phe258 in CYP1A1, and Phe125, Phe226, Gly316, Ala317, Ile386, and Leu497 in CYP1A2, are crucial for the stabilizing interactions of these neolignans with the active sites of CYP1A1 and CYP1A2.