Estudo da Interferência de Neolignanas Bioativas Isoladas e do Extrato Hidroalcoólico de Piper rivinoides Kunth (Piperaceae) na atividade do CYP1A

Abstract

The Piperaceae family, with around 3,600-3,700 species, is one of the most diverse plant lineages, with emphasis on the genus Piper L., with approximately 2,000 species. Phytochemical studies in Piperaceae have revealed several classes of metabolites, including lignans and neolignans, which are known for their rich structural diversity and biological activities such as antiparasitic and antitumor. Neolignans extracted from the leaves of Piper rivinoides Kunth exhibited multiple biological activities, such as leishmanicidal, antifungal, antibacterial and antitumor. Cytochrome P450 (CYP450) enzymes form an extensive family of hemeproteins essential in the metabolism of xenobiotics and endogenous agents. The CYP1, CYP2 and CYP3 families are predominant in oxidative biotransformation, capable of catalyzing different reactions on different substrates. This work investigated the interference of neolignans isolated from Piper rivinoides and its hydroalcoholic extract on the human recombinant enzymes rhCYP1A1 and rhCYP1A2. In vitro tests, Eupomatenoid-5 stood out for its potent inhibitory activity, with an IC50 of 39.5 μM. In vivo assays were carried out in mice of the DBA/2 and Swiss strains. In silico analyzes were conducted on the SwissADME platform and molecular docking was performed using the GOLD© 2022.1 for Windows program with the Hermes viewer. The in vitro results showed that both the isolated neolignans and the hydroalcoholic extract inhibited the activity of rhCYP1A1 and rhCYP1A2. In vivo assays indicated induction of CYP1A in mice subjected to chronic treatment with Eupomatenoid-5. Molecular docking revealed that the fragments in the CYP1A1/A2 cavity are crucial for the interactions of neolignans, especially with eupomatenoid-5 and eupomatenoid-6, which presented the best scores and the highest number of interactions with key residues, such as Phe123, Phe224 and Phe258 (CYP1A1) and Phe125, Phe226, Gly316, Ala317, Ile386 and Leu497 (CYP1A2). These interactions favor aromatic π-π contacts, providing superior docking at the active sites compared to conocarpan. Such results are relevant to understand the pharmacokinetic interactions between benzofuran neolignans and commercialized drugs.