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  • Cytochrome P CYP enzymes plays an essential

    2019-08-09

    Cytochrome P450 (CYP-450) enzymes plays an essential role in pharmacology of drugs and toxicology of xenobiotics. Inhibition of these enzymes may lead to increase plasma levels of a concomitantly administered drug (Lee et al., 2013). It may prolong or reduce the pharmacological effects and increase incidence of drug-induced toxicity or less therapeutic effect (Jarukamjorn et al., 2006). Most of the drugs or herbs are metabolized through CYP3A4 (50%) and CYP2D6 (25%) isozymes (Mukherjee et al., 2011). Several reports exhibited that TMs and phyto-pharmaceuticals also have CYP inhibition or induction effect when administered together with conventional drug (Harwansh et al., 2014). It may alter pharmacokinetic profile which causes less bioavailability or toxicity (Mukherjee and Wahile, 2006). Multidrug combination therapy is very common now for the treatment of various diseases; so drug-drug and herb-drug interaction study is very significant for effective treatment (Pandit et al., 2011a). The food (spice)-drug interaction has also been reported by Pandit et al. (2012). Apart from herb-drug interaction study it is also important to study the heavy metal concentration in the phytomedicine as the continuous uptake and accumulation of heavy metals in different organs may lead to liver, kidney, nervous system, cardiovascular, teratogenic diseases and even cancer (Nema et al., 2014). Besides these, exposure of heavy metals such as lead can decrease the CYP function and it has potential impact on human (Lowry et al., 2012). Chemically CYP450 is heme protein in nature. Therefore formation or activity of CYP450 depends on trace Fmoc-Tyr(tBu)-OH in like Fe. Thus, it is very much necessary to analyse the concentration of this Ayurvedic medicine as suggested by WHO guideline. Standardization of medicinal plant is important for quality control (QC) and active constituent determinations in the plant extract. Similar to the growing interest in research on herbs, there is a rising concern regarding the action of bioactive compounds in plant extracts, on the moderation of human CYP450 activity (Pandit et al., 2011b). It is important to quantify the particular bioactive molecule present in the complex herbal extract. Marker profile and chemical characterization of the medicinal plant is important to maintain quality of natural health product (Mukherjee, 2002). Based on the above facts, attempts have been made for standardization of S. chirata leaf extract along with ursolic acid (marker compound) through RP-HPLC analysis. Additionally the presence of trace and heavy metals in this plant was studied by AAS. The inhibitory effects of S. chirata and ursolic acid on CYP450s (CYP3A4 and CYP2D6) were evaluated through CYP450-CO complex and fluorometric probe substrate assay.
    Materials and methods
    Results
    Discussion Use of herbs as medicine from natural sources is increasing rapidly (Malviya et al., 2010). Very little information regarding herb-drug interaction mediated by CYP inhibition or induction is available. Phytoconstituents present in the extract may inhibit or induce drug metabolizing enzymes thus creating severe herb-drug interaction. Inhibition of these metabolizing enzymes may affect their pharmacological activity and also cause drug induced toxicity (Venkataramanan et al., 2006). Besides drug-drug interaction, herb-drug interaction may also cause drug induced toxicity either by induction or inhibition of drug metabolizing enzymes (Pan et al., 2010). Enzyme inhibition may increase the drug concentration in blood circulation which may potentiate drug induced toxicity. It is important to quantify the phytomolecule present in the extract. It is important to select biomarker (biologically active constituent) which possesses pharmacological property like extract for standardization of S. chirata. Here we select ursolic acid as a biomarker for standardization. Besides standardization it is also necessary to determine whether it contains any hazardous metals and trace elements coming from soil which may induce toxicity or interfere the CYP450 activity if present, beyond the prescribed limit. Ursolic acid present in S. chirata extract was quantified by RP-HPLC analysis and content of trace and heavy metal in the plant material was evaluated by AAS. In this context we did both studies. The heavy metal such as lead can modulate the activity of cytochrome P450 which is reported by Lowry et al. (2012). The exposure can decrease the CYP function. Human study also showed the potential impact of lead on the activity of cytochrome P450. Chemically CYP450 is heme protein in nature. Therefore formation or activity of CYP450 depends of trace element like Fe. In this context we studied the trace elements also. The study result revealed that the concentration of the tested trace and heavy metals present in this plant were below the prescribed limit. Therefore the plant was safe from the tested heavy and traces metals/elements and had no impact on CYP450 enzyme metabolism.