Pharmacokinetic influences of selected phytochemical compounds from herbal medicine used by HIV- positive patients on drugs-metabolising proteins of HIV-1 protease inhibitor drugs.
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Date
2020
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Abstract
Introduction: Sub-Saharan Africa has the highest incidence of HIV/AIDS and AIDS-related
deaths in the world. Although there is currently no cure for the disease, significant progress
has been made in developing antiretroviral drugs (ARVs) that can inhibit disease progression.
However, despite the availability of these ARVs, HIV-positive patients use traditional herbal
medicines (THMs) either alone or simultaneously with conventional ARVs. This
simultaneous usage may cause serious adverse effects due to herb-drug interactions, although
there are also possible positive effects such as the enhanced bioavailability of the ARVs or
possible antiviral activity.
Aim: These potential interactions prompted this study which examined the pharmacokinetic
properties and influences of selected phytochemical compounds (PCs) commonly found in
THMs on drug-metabolising proteins involved in the metabolism of protease inhibitor drugs
(PIs) as well as their potential as inhibitors of HIV-1 protease.
Method: The potential inhibitory activities of fifteen PCs (Epigallocatechin gallate (EGCG),
Fisetin (FST), Ellagic acid (EGA), Cholesta-4,6-dien-3-ol (CHD), Lanosteol (LNT), Benzyl
Isothiocyanate (BIT), Gallic acid, (GA), Isosteviol (IST), Stigmasterol (STG), Phthalic acid
(PTA), Naringenin (NGN), Kaempferol-7-glucoside (K7G), Luteolin (LUT), Geranin (GER),
Apigenin (APG)) against the South African sub-type C HIV-1 protease enzyme and PIs’
drug-metabolizing proteins were investigated, using molecular dynamic (in-silico)
techniques. Furthermore, an in vitro evaluation of the cytotoxicity assays, cell viability
profiles and modulatory influences of the most promising antiviral PCs on the mRNA and
protein expressions of the drug-metabolising proteins in two human cell lines (liver (HepG2)
and kidney (HEK293)) was carried out.
Result: Four of the fifteen PCs (EGCG, K7G, LUT and EGA) were predicted to be potential
inhibitors of HIV-1 protease, as well as inhibitors of cytochrome P450 3A4 (CYP3A4) and Pglycoprotein
P-gp/ABCB1. Results from the in vitro study showed that these four PCs were
not toxic to HepG2 cells at their IC50 (50% cell viability) and IC20 (80% cell viability). ATP
(adenosine triphosphate) levels increased at IC20, with no significant change at IC50. In
addition, no significant change in LDH (lactate dehydrogenase) was seen (with the exception
of LUT).In the HepG2 cells, ABCB1 protein expression (western blot) decreased overall.
While all PCs decreased CYP3A4 protein expression at IC20, (with the exception of LUT)
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protein expression increased at IC50. mRNA levels were decreased for EGCG and K7G at
IC20. InHEK293 cells, all PCs were non-toxic. ATP concentrations were similar to the control
except for EGCG which decreased at IC20, and K7G which increased at IC50. LDH
concentration decreased when exposed to the PCs at IC20, but a significant (p < 0.05) increase
was recorded in LUT IC50. ABCB1 protein expression increased at both IC20 and IC50
concentrations, although LUT and EGA mRNA expression decreased at IC50. The decreased
protein activities of CYP3A4 in K7G IC50 and LUT IC20 correlates with increased
intracellular ATP.
Conclusion: The study therefore suggests that EGCG, K7G, LUT and EGA could decrease
the biotransformation of drugs, and eventually increase drug plasma concentrations in the
systemic circulation. These natural compounds that can serve as inhibitors of drugmetabolizing
proteins and the HIV-1 protease enzymecould be useful in the treatment of
HIV-1.
Description
Doctoral Degree. University of KwaZulu-Natal, Durban.