Proposed Reductive Metabolism of Artemisinin by Glutathione Transferases in vitro

Naik, Yoseshkumar. S (2001) Proposed Reductive Metabolism of Artemisinin by Glutathione Transferases in vitro.

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journal for proposed reductive metabolism,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,the support of the International Program in Chemical Sciences (IPICS), Uppsala University, Sweden, The Swedish Natural Science Research

Item Type: Article
Uncontrolled Keywords: Glutathione -transferases,metabolism,arternisinim,reduction
Divisions: Universities > State Universities > National University of Science and Technology
Depositing User: Mr. Edmore Sibanda
Date Deposited: 01 Dec 2015 01:02
Last Modified: 01 Dec 2015 01:02

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