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  • Because flavonoids are widely considered to contribute

    2020-05-29

    Because flavonoids are widely considered to contribute to health benefits in humans, including anti-inflammatory, antibacterial, antiviral, anticancer, antiplatelet properties, and free radical scavenging capacity (Xiao et al., 2011), efforts have frequently been made to increase their bioavailability by, for example, enhancing metabolic stability. It was shown that methylated compounds were more stable compared to unmethylated compounds (Wen and Walle, 2006). Intensive research on methods to enhance flavonoid bioavailability is underway (Hu, 2007, Sansone et al., 2011). However, high concentrations of bioavailable flavonols are not always beneficial, as they may diminish or even adversely affect metabolism of commonly prescribed drugs due to their interaction with drug-metabolizing cytochrome P450 (CYP450) enzymes. Ability of flavonols to modify CYP450 activity might result in unpredictable health consequences when flavonols are ingested simultaneously with drugs (Hodek et al., 2002, Tarirai et al., 2010). Regulation of CYP450 and its importance for herb-drug interactions has been the focus of numerous studies. Several studies have reported quercetin’s ability to reduce CYP2E1 levels and activity in vitro and in animal models (Ekstrand et al., 2015, Surapaneni et al., 2014, Tang et al., 2013). Activity of CYP3A4, which is regarded as one of the most important Phusion high-fidelity DNA polymerase since it is involved with the metabolism of approximately 50% of prescribed drugs, is also affected by the presence of flavonols (Savai et al., 2015, Subehan Usia et al., 2006, Vijayakumar et al., 2015). These interactions are an important clinical concern and have to be carefully examined, especially today, when many people self-medicate using high concentrations of flavonols and other phenolic compounds in form of extracts and food supplements (Tarirai et al., 2010). It is well established that differences in response to pharmaceuticals can differ among individuals based on genetic variation of a polymorphic enzyme. For example, this was observed in racially and ethnically distinct subgroups of the US population (Temple and Stockbridge, 2007). Variation related to gender may also be of consideration. Thus, in studies on modulation of CYP450 activity by flavonols assessment of both sexes are desired. We have previously shown that the flavonols myricetin, isorhamnetin, and quercetin affected the activities of CYP1A1, CYP3A, and CYP2E1 in a gender-dependent manner in pigs. To the best of our knowledge, gender-related differences in flavonoid interactions with human CYP450 have not been studied. The aim of the present study is to investigate gender-related differences in the changes of human CYP2E1 and CYP3A4 activity in the presence of the dietary flavonols quercetin, isorhamnetin, and myricetin. CYP1A1 activity was not included in this study because it is essentially an extrahepatic enzyme and expressed only at very low levels in human liver (Paine et al., 2006).
    Material and methods
    Results The Vmax (nmol/min/mg) and Km (μM) values for PNPH and BFC activities in each microsomal pool were generated from the Michaelis–Menten non-linear regression equation (Table 1). Quercetin, but not myricetin or isorhamnetin, inhibited PNPH activity in human recombinant cDNA-expressed CYP2E1 in a concentration-dependent manner (Fig. 2). The remaining activity was 46.7% in the presence of 128μM of quercetin. Further investigations to explore the inhibition mechanism of quercetin using substrate concentrations from 0.0025 to 0.4mM revealed a competitive mode of inhibition with the Ki=52.1±6.31μM. Overall, the degree of inhibition of PNPH activity by quercetin in the human microsomes slightly differed between genders (i.e., higher in the microsomes from male pools) (Fig. 3). However, the degree of inhibition did not reach 50%. The average remaining PNPH activity in the presence of quercetin ranged from 56.5 to 65.5% in male pools and from 65.4 to 96.5% in female pools. Including a pre-incubation step did not further decrease PNPH activity indicating reversible nature of this slight inhibition (Fig. 3).