In vitro assessment of cytochrome P450 and drug transporters modulation by polyphenolic constituents of cyclopia genistoides
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Date
2019
Journal Title
Journal ISSN
Volume Title
Publisher
University of Zululand
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.
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.
Keywords
Cytochrome, Polyphenolic constituents, Cyclopia genistoides, Herbal concoctions, Traditional medicines -- South Africa, Ancient remedies -- South Africa