Another major representative of the flavonol myricetin also

Another major representative of the flavonol myricetin also inhibited porcine CYP450 in a gender-related manner (Ekstrand et al., 2015). In the present study, myricetin did not affect CYP2E1 and inhibited CYP3A activity with a higher degree of inhibition in the pools from female individuals. CYP3A activity in the pools from males showed either slight (remaining activity above 50%) or no inhibition. Similarly to the quercetin effect on CYP2E1, the Ki values for myricetin were larger than its maximal physiologically relevant concentrations, indicating that myricetin is unlikely to inhibit the activity of CYP3A in vivo. The structure of flavonols is an important factor that determines the flavonol effect on CYP450 activity (Ho et al., 2001, Hodek et al., 2002). The methylated form of quercetin, isorhamnetin, did not affect either CYP2E1 or CYP3A in the present study (remaining activity is above 50% in all pools). High individual variations in the activity of drug metabolizing px12 are well known (Pinto and Dolan, 2011) and contribute to low reproducibility of data on drug interactions. The observed variation in the response of CYP450 activity to bioactive compounds between pools of human liver microsomes presents a challenge when performing studies on herb-drug interactions. These variations are, however, not due to the gender.
Conclusion
Conflict of interest
Acknowledgments This study was supported by the Swedish University of Agricultural Sciences, NJ faculty. Support was also given to Vladimir Zlabek by the Ministry of Education, Youth and Sports of the Czech Republic through projects “CENAKVA” (No. CZ.1.05/2.1.00/01.0024) and “CENAKVA II” (No. LO1205 under the NPU I program).
Introduction Rat cytochrome P450 (CYP) subfamily CYP3A constitutes about 20% of the total CYP protein in the liver. Among CYP3A isoforms, CYP3A2 (male-dominant) is the main constitutive liver enzyme, while the expression of CYP3A1 is very low [1]. Rat CYP3A2 exhibits a 73% homology of the amino acid sequence, some substrate preference and functional analogies to human CYP3A4, which is responsible for the oxidative metabolism of more than 60% of currently used drugs, such as macrolide antibiotics, calcium channel antagonists and psychotropics, as well as endogenous substances including testosterone, progesterone and androstenedione [6, 27]. In general, catalytic competence of rat CYP3A2 and human CYP3A4 is similar. Rat CYP3A2 and human CYP3A4 are involved in the metabolism of erythromycin, nifedipine, lidocaine, testosterone, aflatoxin B1 and benzo(a)pyrene [6, 18]. 6β-Hydroxylation of testosterone in humans and 2β- and 6β-hydroxylation of testosterone in rats are used as marker reactions for studying CYP3A activities [6, 16]. Moreover, the human and rat CYP3A subfamily isoforms are inhibited by ketoconazole, troleandomycin and erythromycin [5, 21]. The CYP3A genes are regulated physiologically by glucocorticosteroids, growth hormone, thyroid hormones and cytokines [13, 20, 30]. It has been shown that glucocorticoid receptor (GR), pregnane X receptor (PXR), constitutive androstane receptor (CAR) and vitamin D receptor (VDR) play an important role in the regulation of CYP3A genes [2, 6]. Both PXR and CAR act as dimers with retinoid acid X receptor (RXR). GR may contribute to CYP3A induction via direct or indirect molecular mechanism, including functional cross talk between GR-, PXR- and CAR-signaling pathways [4, 19].