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Top1. Introduction
The family of cytochrome P450 (CYP) proteins is widely distributed in all kingdoms of life, from bacteria, archaea, and viruses to higher plants and animals. The substrates of CYP proteins can be very varied, including endogenous compounds produced by cell metabolism, and exogenous substances such as biogenic amines (Sánchez-Jiménez et al., 2013), cytostatic agents (Evteev et al., 2006), and steroids (Yamazaki et al., 1998). CYPs are monooxygenases that contain a heme group, which catalize a variety of reactions, such as hydroxylation, epoxidation, oxidation, reduction, deamination, dehalogenation, dealkylation, dehydrogenation, and demethoxygenation (Ortiz de Montellano&De Voss, 2005; Gillam&Hunter, 2007).
CYP3A4 is the most abundant human isoform. CYP3A4 is found in the liver and it metabolizes, completely or partially, around 45-60% of clinical drugs (Li et al., 2018). Therefore, the regulation of its expression and/or activity is clinically relevant (Zanger&Schwab, 2013). Some members of the flavonoid family, including proanthocyanidins (Lobayan et al., 2009) and bioflavonoids (Mercader&Pomilio, 2011), that are present in fruits, vegetables, and dietary supplements, have demonstrated to possess the ability to modify the activity of the CYP system (Miron et al., 2017), thus changing the pharmacodynamics and pharmacokinetics of many commercial drugs (Moon et al., 2006; Dreiseitel et al., 2008).
Anthocyanins belong to the family of flavonoids, being widely distributed in nature as hydrosoluble pigments responsible for red, blue, purple, and violet colors of flowers, bracts, leaves, fruits, and also stems (Cheynier, et al., 2015; Pomilio&Mercader, 2018). Anthocyanins are mainly found as glycosylated derivatives of the anthocyanidins cyanidin, delphinidin, malvidin, pelargonidin, peonidin, and petunidin (Pomilio&Mercader, 2018). The oral administration of anthocyanin-containing fruits, extracts, and pure compounds has shown to be effective in the prevention and/or treatment of some diseases, such as cardiovascular disorders, diabetes, arthritis, and cancer, due to the antioxidant and anti-inflammatory properties (Bentz et al., 2017; Putta et al., 2018; Chen et al., 2018; Pomilio&Mercader, 2018). A part of the efficiency of chemotherapeutic and antimicrobial agents after the administration of anthocyanins and derivatives is due to their positive activity in multidrug resistance (Bentz et al., 2017; Pomilio&Mercader, 2018).
Previously, Dreiseitel et al., 2008 reported that this kind of compounds and their derivatives, for example, aglycons and procyanidins have shown concentration-dependent inhibition of CYP. On the other hand, the same authors suggested that the number of sugar moieties showed a decrease in the effects of anthocyanidins on CYP3A4, which underscores the need for more detailed data on structure-activity relationships. The anthocyanins isolated from the fruits of Aronia melanocarpa have the ability to inhibit the mutagenic activity of α-benzopyrene and 2-aminofluorene in the Ames test (Gasiorowski et al., 1997), thus demonstrating the antimutagenic properties of these compounds. Furthermore, the ability to inhibit CYP of this group of compounds could be considered antimutagenic due to the fact that these enzymes contribute to the carcinogenesis in several organs, and increase toxicity and DNA damage.
This has been the goal of many modeling studies (Langowski&Long, 2002; Kirton, 2002), based on the framework mentioned above, and the crucial role of the CYP enzyme set. Therefore, interest has arisen in performing a predictive and selective search within the family of anthocyanins, several precursors and derivatives, through studies of Quantitative Structure-Activity Relationships (QSAR) (Bentz, et al., 2017; Duchowicz et al., 2019), to obtain a mathematical model with predictive power by relating the molecular structure, encoded within the so-called molecular descriptors (Todeschini&Consonni, 2009), to a biological activity of interest (Pomilio et al., 2019).