Proposed Reductive Metabolism of Artemisinin by Glutathione Transferases in vitro
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Date
2001-01-18
Journal Title
Journal ISSN
Volume Title
Publisher
The Harwood academic publishers imprint,
Abstract
Artemisinin is a sesquiterpene lactone containing an
endoperoxide bridge. It is a promising new antimalarial
and is particularly useful against the drug resistant
strains of Plasmodium fakiparum. It has unique antimalarial
properties since it acts through the generation of
free radicals that alkylate parasite proteins. Since the
antimalarial action of the drug is antagonised by
glutathionc and ascorbate and has unusual pharmacokinetic
properties in humans, we have investigated if
the drug is broken down by a typical reductive reaction
in the presence of glutathione transferases. Cytosolic
glutathione transferases (GSTs) detoxlfy electrophilic
xenobiotics by catalysing the formation of glutathione
(GSH) conjugates and exhibit glutathione peroxidase
activity towards hydroperoxides. Arternisinin was
incubated with glutathione, NADPH and glutathione
reductase and G~TiSn a coupled assay syste&analogous
to the standard assav scheme with cumene hv,d rover- L oxide as a substrate df GSTS. Arternisinin was shown to
stimulate NADPH oxidation in cytosols from rat liver,
kidney, intestines and in affinity purified preparations
of GSTs from rat liver. Using human recombinant GSTs
hetelorogously expressed in Escherichia coli, artemisinin
was similarly shown to stimulate NADPH oxidation
with the highest activity observed with GST MI-1.
Using recombinant GSTs the activity of GSTs with artemisinin
was at least two fold higher than the reaction
with CDNB. Considering these results, it is possible that
GSTs may contribute to the metabolism of artemisinin
in the presence of NADPH and GSSG-reductase We
propose a model, based on the known reactions of
GSTs and sesquiterpenes, in which (1) artemisinin
reacts with GSH resulting in oxidised glutathione; (.2)
the oxidised glutathione is then converted to reduced
glutathione via glutathione reductase; and (3) the latter
reaction may then result in the depletion of NADPH
via GSSG-reductase. The ability of artemisinin to react
with GSH in the presence of GST may be responsible
for the NADPH utilisation observed in vitro and suggests
that cytosolic GSTs are likely to be contributing to
metabolism of artemisinin and related drugs in vivo
Description
journal for proposed reductive metabolism
Keywords
Glutathione -transferases, metabolism, arternisinim, reduction
Citation
STANLEY MUKANGANYAMAa, YOGESHKUMAR S. NAIKa, MIKAEL WID ERST., (2001) Proposed Reductive Metabolism of Artemisinin by Glutathione Transferases in vitro. the Harwood Academic Publishers imprint,