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  • br Conclusions The present study demonstrated that

    2019-07-13


    Conclusions The present study demonstrated that CuE possesses strong hepatotoxicity. CuE is not only a mechanism-based inhibitor of human CYP3A4, but also inhibits P-gp activity in vitro. In whole animal studies, CuE induces CYP3A and P-gp after a long-term treatment but inhibits the activities of CYP3A and P-gp after a short-term acute dosing. Therefore, CuE as a dual functional regulator of both CYP3A and P-gp may cause complex drug-drug interactions. Further systematic study in humans is needed to identify the interactions of CuE-containing medicine with drugs that interact with CYP3A and P-gp, and then adjust proper dosage to avoid potential problems and make sure the minimal adverse effects.
    Conflict of interest
    Introduction The Cytochrome P450 (CYPs) (+)-Usniacin comprising a CYP superfamily are hemoproteins present in all domains of life [1]. CYPs generally act as oxidising agents in a variety of metabolic and biosynthetic reactions, including detoxification and regulatory processes [2]. In vertebrate detoxification system, the enzymes of CYP3A subfamily dominate both from expression and activities perspective [3], [4]. CYP3A4 is the most significant and abundant enzyme among xenobiotic metabolising enzymes of CYP3A subfamily. CYP3A4 has a broad substrate spectrum, expressed predominantly in liver and small intestine and is believed to metabolise about 50% of drugs in humans [5]. The presence and level of expression of these enzymes influences the tissue\'s capacity to metabolise and/or to detoxify the xenobiotics, efficiency of systemic clearance and reflect the bioavailability of therapeutic drugs [6]. The world\'s largest living reptiles, saltwater crocodiles are important models for the evolutionary history along with their great ecological, sociological and commercial significance [7], [8]. This species is farmed in Australia to ensure conservation and for their highly valued skins [9]. Research regarding drug metabolism and CYPs in the saltwater crocodiles is scarce with only two studies identifying and investigating few functional aspects [10], [11] making it impossible to evaluate the safety and/or toxicity of xenobiotics. The functional characteristics of enzymes can be elucidated by understanding the molecular basis of these enzymes in relation to its 3D structure [12]. The diverse CYP superfamily with sequence variability yet similar tertiary structures [13] possess the conserved structural elements involved in protein folding [14]. The knowledge of 3D structures of CYPs, their substrate recognition, binding sites, substrate access, exit channels, haem domain and their functions is indispensable for understanding of structural divergence and adaptations for membrane binding and functional diversity throughout evolution and the contemporary drug design [15], [16], [17], [18], [19], [20]. In addition to experimental methods, highly reliable 3D structures and their functions have been predicted on the basis of computational techniques using either single or multiple experimentally determined structures as templates [21].
    Materials and methods
    Results
    Sequence and structural analysis of CYP3A163 All the benchmark motifs for eukaryotic CYPs and CYP3A subfamily as described by Nelson [27] and the characteristic features of microsomal and xenobiotic metabolising CYPs have been observed and modelled with high quality. This signifies its structural and functional similarities with CYP3A subfamily despite the evolutionary distances from other species. First 27 residues represent the transmembrane anchor that is common in all eukaryotic CYPs [28]. The proline rich motif of microsomal CYPs PPGPXPXPXXGN (PGPKPMPFFGT, 39-49) with a role in modulation of protein folding and substrate access [29] starts with hydrophobic isoleucine (I-38) in CYP3A163. The presence of eukaryotic conserved tripeptide KYG (67-69) [27] suggests its evolutionary relation with the ancient eukaryotic CYPs. Another conserved motif for eukaryotic CYPs WXXXR, (WKRIR, 126-130) and the diagnostic feature for CYP3A subfamily, GAYSMDVV (177-184) correspond to helix-C and helix-E respectively. The conserved sequence motifs (CSM) for xenobiotic metabolising CYP families 1-3, located between helices E and H have been identified as CSM7 (FGVNIDS, 189-195) and CSM10 XXFPFL (WAFPFL, 224-229) implying similar role in protein modulation for substrate access or egress to the active site [12]. The absence of CSM8 and CSM11 indicates the variations of these channels for size of ligands, shape and hydrophobicity of CYP3A163.