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In vitro assessment of cytochrome P450 and drug transporters modulation by polyphenolic constituents of cyclopia genistoides

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dc.contributor.advisor Bowles, S.L.
dc.contributor.advisor Kappo, A.M.P.
dc.contributor.author Mchunu, Nonkululeko Purity Nokuphila
dc.date.accessioned 2019-07-16T07:52:05Z
dc.date.available 2019-07-16T07:52:05Z
dc.date.issued 2019
dc.identifier.uri http://hdl.handle.net/10530/1750
dc.description A dissertation submitted in the partial fulfilment of the requirements for the Degree of Master of Science in the Department of Biochemistry, Faculty of Science and Agriculture at the University of Zululand, 2019. en_US
dc.description.abstract Historically, medicines were administered in the form of herbal concoctions, and this is still true for many traditional medicines. These ancient remedies are often consumed straight from the bush/bark or leaf, ground up as powders or brewed as teas. In these forms, the active ingredient, as part of the mixture, if often found at low concentrations and have a low bioavailability. The primordial use of natural medicine is growing in popularity and as science has advanced, chemists have shown it possible to extract active ingredients from natural sources to make more potent medications under the term “nutraceutical”. As the health-conscious increase “superfoods” into their daily dietary intake, it has also been shown that a large portion of the South African populations will use natural products as their primary source of medication and more frequently as adjunctive therapeutics. Herb-drug interactions (HDI) are acknowledged as a growing public health problem that can lead to life-threatening adverse drug reactions (ADR). When boosting the efficacy of herbal products, methods are employed to produce products enriched in bioactive phytochemicals, However, the increased exposure to these bioactive phytochemicals poses the risk of HDI should the user be simultaneously prescribed conventional drugs. The potential for ADR originating from HDI should require assessment before herbal products are made available on the market, but no current legislature makes this testing mandatory. Cyclopia genistoides has shown potential to be developed into an antidiabetic nutraceutical because of its α-glucosidase inhibitory activity and high phenolic content. In this study, we assessed the effect of a Cyclopia genistoides extract for its interaction with cytochrome P450 (CYP) enzymes and drug transporters to investigate whether the use of C. genistoides extract or its bioactive phenolic constituents has the potential for herbdrug interactions. The potential for hepatotoxicity of a methanol C. genistoides extract, xanthone and benzophenone enriched fractionations and associated pure compounds (mangiferin, isomangiferin, 3-β-D-glucopyranosyl-4-β-D-glucopyranosyloxyiriflophenone (IDG) and 3-β-D-glucopyranosyliriflophenone (IMG)) was assessed using C3A liver cells. The inhibitory effects of these test entities on major CYP isoforms were assessed using III Vivid® blue screening kits in both time and concentration-dependent assays. qRT-PCR was performed using Taqman probes in order to investigate the modulatory effect of C. genistoides constituents on the expression of drug transporters (SLCO1B3, ABCB1 and ABCG2). Translation of these drug transporter genes was confirmed through Western blot analysis. C. genistoides was deemed non-toxic to C3A hepatocytes at the concentrations tested. ARC188 showed inhibitory activities on all CYP isoforms tested (50.27%, 72.47%, 70.68%, 50.48% and 78.49% inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, respectively). ARC188X inhibited CYP1A2, CYP2D6 and CYP3A4 by 57.15%, 56.56% and 50.61%, respectively. Mangiferin inhibited CYP 3A4 (60.83 % inhibition), CYP2D6 (52.12% inhibition) and CYP2C9 (82.08% inhibition). While ARC188B only inhibited CYP3A4 (53.28%) and the benzophenone pure compounds (IMG and IDG), and isomangiferin had no inhibitory effects on CYP activity. All tested C. genistoides constituents up-regulated the efflux drug transporter ABCB1. Xanthone-enriched extracts, especially those with a high mangiferin content, show potential towards HDI especially with antidiabetic drugs such as sulfonylureas and warrant further investigation into the possibility of ADR. en_US
dc.language.iso en en_US
dc.publisher University of Zululand en_US
dc.subject Cytochrome en_US
dc.subject Polyphenolic constituents en_US
dc.subject Cyclopia genistoides en_US
dc.subject Herbal concoctions en_US
dc.subject Traditional medicines -- South Africa en_US
dc.subject Ancient remedies -- South Africa en_US
dc.title In vitro assessment of cytochrome P450 and drug transporters modulation by polyphenolic constituents of cyclopia genistoides en_US
dc.type Thesis en_US


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