• 2018-07
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  • P has three subfamilies CYP


    P450 has three subfamilies (CYP1, CYP2, and CYP3), which contribute largely to the oxidative biotransformation of xenobiotics that include most drugs, dietary chemicals, and environmental pollutants. The CYP1 enzymes have great importance in the bioactivation of mutagens and its isoforms are capable of activating aromatic amines, therefore extrahepatic and cell line-specific regulation of CYP1A1 and CYP1B1 are major determinants of chemosensitivity or resistance [6]. It is proved that CYP1A1 is the covalently bound protein (50 kDa) in sensitive cell lines [7]. A prior study demonstrated that benzoxazoles and benzothiazoles, as CYP1A1 inhibitors, show anticancer activities in sensitive (Z)-4-Hydroxytamoxifen [8], [9]. Of the xenobiotic metabolizing P450s, the two members of the 1A subfamily, CYP1A1 and CYP1A2, have attracted particular attention given their ability to both detoxify and metabolically activate chemical carcinogens. CYP1A2 is constitutively expressed in liver, whereas CYP1A1 has low or absent constitutive expression in liver. In contrast, CYP1A1 is found in lung, lymphocytes, placenta and skin. Notably, polycyclic aromatic hydrocarbons (e.g. those found in cigarette smoke) induce CYP1A1 expression in these tissues and in liver [10]. Thus, the constitutive and inducible expression of CYP1A1 and CYP1B1 are considered to be important determinants of carcinogenesis, although the exact relationship between CYP1 expression and chemically induced carcinogenesis remains to be established [11]. Computational approaches have helped in understanding substrate and inhibitor binding to the major human CYPs 1A2, 2B6, 2C9, 2D6, 3A4 as well as other CYPs and additionally complement homology models for these enzymes. Later quantitive structure-activity relationships for oxidation by CYPs were correlated with hydrophobic and steric parameters of substrates [12]. The experimental determination of 3D structures of mammalian cytochromes P450 has proved to be complex because they are membrane-bound proteins. Several computational approaches have been used to characterize the molecular properties of substrates and inhibitors of the CYP1A2 enzyme. Recently, a model of CYP1A2h was built with the aim of improving our understanding of this important enzyme [13]. Lozano et al. have reported a three-dimensional quantitive structure-activity relationships (3D-QSAR) methods based on ligand–receptor complexes to study a series of CYP1A2h ligands [14]. Similarly, CYP450 1A1 homology models have been reported based on several crystallographic templates [15], [16], [17], [18], [19], [20], [21], [22].
    Results and discussion
    Experimental protocols
    Introduction The combination of synthetic drugs and traditional Chinese medicines (TCMs) is one of the most important approaches in clinical treatment in China. While in most cases, co-administration of these drugs is actually being practiced lacking research evidence on drug-drug interaction (DDI). Case reports and clinical studies outside of China have highlighted the existence of a number of clinically important herb-drug interactions, concerned mainly with St John\'s wort, Echinacea, garlic, gingko, ginseng, goldenseal, and milk thistle, although cause-and-effect relationships have not always been established (Hermann and von Richter, 2012, Izzo and Ernst, 2009, Izzo et al., 2016). A number of investigations on animals in recent years also indicated that administration of either herbal ingredients (Pan et al., 2011, Qin et al., 2015) or compound formulas (Geng et al., 2015, Ohnishi et al., 2002, Ueng et al., 2002) of TCMs could bring significant impact on cytochromes P450 enzymes. By these still limited research data, TCMs exerts no unusual safety in terms of DDI, but the likelihood of interactive risk due to shortage of enough research concerned. Sailuotong (SLT) is a standard herbal preparation composed of ginseng (the dried root and rhizome of Panax ginsengC. A. Meyer), ginkgo (the leaves of L.), and saffron (thestigmaof Crocus sativus L.), with ginseng ginsenosides, ginkgo biloba flavonoids and terpenoids along with crocins as major active ingredients. SLT is formulated for the treatment of vascular dementia based on the function of its herbal components. Ginseng is widely used as a tonic for restoration of strength in China. Its function of cognition-enhancing, anti-anxiety and anti-depression have been recorded in ancient medical literature of Bencaogangmu in 16th century. Ginkgo and saffron have been traditionally used for a long time as medicines with main effect of promoting blood circulation and removing blood stasis according to their function described in Chinese Pharmacopoeia. In recent decades, commercial extracts of ginkgo has been most frequently prescribed as preparations for improving cerebral blood circulation and enhancing memory due to their vasodilatation, anticoagulant, anti-oxidative, and anti-inflammatory activities (Luo, 2001). Accumulating evidence indicated the efficacy of saffron in attenuating memory disorders related to AD, cerebral injuries, or schizophrenia both in animal models and clinical observation (Pitsikas, 2015). Pharmacological studies on SLT have demonstrated its effectiveness in treating focal cerebral ischemia and focal cerebral ischemia/reperfusion in rats (Xu et al., 2012, Xu et al., 2008, Zhang et al., 2015, Zheng et al., 2010). International clinical trials on efficiency of SLT have been carried in China and Australia cooperatively (Liang et al., 2014, Steiner et al., 2016). The outcome of two preliminary pilot trials in Australia showed SLT has the potential to improve working memory performance in healthy adults and greater effects than placebo on VD assessment scale-cognitive subscale in VD patients (Liu et al., 2007, Steiner et al., 2016). Vascular dementia is a chronic disease, requiring long-term drug treatment. It commonly occurs in elderly people, who frequently suffer from other concurrent chronic diseases and are thus prescribed a variety of drugs. Consequently, adverse metabolic DDIs may be encountered in these patients.