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  • JWH 015 CYP A is involved in the enzymatic oxidation


    CYP3A is involved in the enzymatic JWH 015 of many therapeutic agents [29]. The activity of BFCOD has been used to monitor CYP3A activity in humans [30], pigs [31], mice [32], and fish [23]. The predominant isoform expressed in the human liver is CYP3A4 [33]. In pigs, CYP3A29 contributes most to CYP3A activity, and it often metabolizes the same substrates as human CYP3A4 [34]. Mice have also shown similarity to humans in CYP3A activity [35]. The most abundant isoform of this subfamily in mice is CYP3A11 [36]. Investigations of piscine CYP3As show that fish contain CYP3A-like activity that is related to mammalian CYP3A (e.g., human CYP3A4 and rat CYP3A1) [37]. In this study, inhibition of BFCOD activity by naringenin followed similar patterns in these four species. Considering the high homology between human CYP3A4, porcine CYP3A29, and murine CYP3A11, a similarity in the response to bioactive flavonoids is not surprising. Indeed, BFCOD activity was inhibited by naringenin in a competitive manner in all mammalian species. This result is in good agreement with a previous study [15]. Despite obvious similarities in inhibition patterns between the four CYP3As, there were significant between-species differences in in vitro kinetic parameters, particularly in Km values, indicating a species-specific affinity of the substrate BFC for the enzymes. The comparatively low Vmax in fish can be partially connected to differences in incubation temperature (37°C for mammals and 25°C for fish); however 25°C is most often used for fish CYP450 incubations. It can also be connected to the comparatively low CYP3A-like protein concentrations in fish microsomal fractions. This requires further study. The pathway of biosynthesis of naringenin and naringin and their fates in the human body have recently been clarified [38], [39]. It is generally believed that naringin mainly inhibits the CYP3A enzyme. However, naringenin was a more potent inhibitor of CYP1A and CYP3A isoforms in human hepatic microsomes than its precursor. The IC50 value of CYP3A inhibition by naringenin is 10-fold lower than that for naringin in human hepatic microsomes [16], [40], [41], and it varies from 8.8μM [40] to 188μM [16] in human hepatic microsomes. These variations in IC50 are likely a result of the chemical structures of the substrate, enantiomers of the flavone, and model species [17]. Furthermore, grapefruit juice showed inhibition of CYP3A in vitro under conditions that do not allow for formation of naringenin, meaning that naringin and naringenin were not the sole contributors to the effect [42]. The mechanisms of these interactions are only partly understood. A study that attempted to elucidate the interaction between diosmin and the CYP450 system showed that diosmin is an agonist of the aryl hydrocarbon receptor, causing a potent increase in CYP1A1 activity [43]. When observing increased metronidazole concentrations in human blood, it was assumed that diosmin could interact with CYP3A4 and/or CYP2C9 [44]. The present study demonstrates that BFCOD activity is not affected by the presence of diosmin. To our knowledge, neither in vivo nor in vitro inhibitions by potential flavones such as diosmin, naringenin, and naringin on the piscine CYP450 system have been studied. The European Food Safety Authority concluded, based on available information of naringin effects in target organisms, that its presence in an aquatic environment does not pose any risk for non-target species, yet the effects of naringenin are still under discussion [45]. Contrary to naringin and naringenin, which are nutritional supplements, diosmin is a semisynthetic drug used for treatment of vascular diseases and hemorrhoids [46]. In France, consumption of diosmin was 373544kg in 2004 [47]. In this case, the calculated predicted environmental concentration of diosmin (when assuming metabolism is negligible in waste water treatment plant influent [WWTPinf]) is 68μg/L in France [48]. This concentration might pose adverse effects on fish health [49]. Our results showed that naringin and diosmin do not affect fish CYP3A-like activity in rainbow trout. While diosmin did not exceed 50% inhibition in fish, it could be of physiological significance. Thus, the potential effects of this inhibition require further research. This is the first study of the effects of naringenin on the fish CYP450 system. We found that BFCOD activity was non-competitively inhibited. This is not the first comparative study where a different manner of CYP3A activity inhibition was found. For example, ketoconazole can competitively inhibit CYP3A activity in fish, while in pig hepatic microsomes it non-competitively inhibits activity [24]. The Ki value for naringenin inhibition of BFCOD activity was relatively low in fish compared to mammals. Naringenin can be prioritized in environmental risk assessment tests. In vivo studies on the effects of naringenin on physiological processes in fish are warranted.