Some studies have been conducted on the activities http
Some studies have been conducted on the activities of CYP450 [, , , ]. For example, Chen et al. reported that low-dose aspirin induced the in vivo activity of CYP2C19 in healthy subjects , Krasniqi et al. reported that CYP2C8*3 and CYP2C9*2*3 variants correlated with ibuprofen-induced hepatotoxicity and gastrointestinal bleeding . Nevertheless, the activity of other CYP450 isozymes and pharmacokinetics changes remain unclear, especially with long-term administration. In thepresent study, the metabolic activity and pharmacokinetics of five liver CYP450 enzymes (CYP1A2, CYP2C9, CYP2B6, CYP2D6 and CYP3A4) were simultaneously studied using a cocktail approach. The diagnostic value of those five CYP450 enzymes was evaluated by Fisher discriminant by using pharmacokinetic data. Moreover, the ultrastructural alterations of liver 3576 were investigated, providing a different perspective on aspirin and ibuprofen.
Conflicts of interest
Acknowlegements This work was supported by fund of Natural Science Foundation of Zhejiang province (LY16H300005), the Health Department of Zhejiang province (2015KYA154); Public Project of Wenzhou Science and Technology Bureau (Y20160304) the social development of Jinhua Technology Bureau (key projects: 2016-3-013, public service project: 2016-4-005).
Introduction Cytochrome P450 (CYP450) enzymes catalyze an unparalleled diversity of primary and secondary metabolic reactions across all domains of life. Two single electron transfers and activation by molecular oxygen of a resting FeIII bound to a porphyrin scaffold in the CYP450 enzyme active site leads to the formation of an electrophilic FeIV=O+● oxoferryl species that can homolytically cleave XH bonds (X=C, N, O, and S) in organic substrates to generate a radical intermediate. The substrate radical can then participate in myriad downstream reactions with regio- and stereospecific control exercised by the CYP450 enzyme active site. CYP450 enzymes have evolved to take full advantage of the redox potential of the oxoferryl species by accommodating a wide diversity of substrates to match the diversity of reactions that they catalyze. Several excellent reviews that describe the underlying iron-porphyrin activation scheme for CYP450 enzymes and the ensuing reactions that they catalyze are available (Denisov, Makris, Sligar, & Schlichting, 2005; Podust & Sherman, 2012; Poulos, 2014; Rudolf, Chang, Ma, & Shen, 2017; Tang, Zou, Watanabe, Walsh, & Tang, 2017). Efforts to engineer CYP450 enzymes to catalyze reactions that fall outside the current scope of these enzymes further highlight their tremendous catalytic prowess (Girvan & Munro, 2016; McIntosh, Farwell, & Arnold, 2014). CYP450 enzymes require two partner enzymes—a ferredoxin-NAD(P)+ oxidoreductase and a ferredoxin—for activity. These reaction partners channel two electrons from a NAD(P)H donor via a single electron adapter (flavin), finally delivering two single electrons sequentially to the iron-porphyrin reaction center in the CYP450 enzyme active site via the ferredoxin Fe–S cluster (Poulos, 2014; Tripathi, Li, & Poulos, 2013). While numerous variants to this theme exist, the underlying electron transfer route from NAD(P)H to the iron-porphyrin reaction center is fairly conserved (Guengerich & Munro, 2013). Aryl crosslinking is a well-represented transformation among the reactions catalyzed by CYP450 enzymes. Perhaps the most celebrated examples for CYP450-mediated aryl crosslinking reactions are the installation of the intra- and intermolecular ether and carbon–carbon bonds in the biosynthesis of glycopeptide antibiotics such as vancomycin (1, Fig. 1) and plant alkaloids such as berbamunine (2) and magnoflorine (3) (Ikezawa, Iwasa, & Sato, 2008; Kraus & Kutchan, 1995; Mizutani & Sato, 2011; Yim, Thaker, Koteva, & Wright, 2014). Furthermore, a dedicated CYP450 enzyme recruitment domain has recently been described to be embedded within the nonribosomal peptide synthetases that catalyze the formation of the glycopeptide antibiotics (Brieke, Peschke, Haslinger, & Cryle, 2015; Haslinger, Peschke, Brieke, Maximowitsch, & Cryle, 2015; Peschke, Gonsior, Sussmuth, & Cryle, 2016).