Browsing by Author "Mukanganyama, Stanley"

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    Inhibition of Glutathione S-Transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance.
    (Wiley-Liss, Inc., 2001-08-06) Mukanganyama, Stanley; Widersten, Mikael; Naik, Yogeshkumar S.; Mannervik, B.; Hasler, Julia A.
    A strategy to overcome multidrug resistance in cancer cells involves treatment with a combination of the antineoplastic agent and a chemomodulator that inhibits the activity of the resistance-causing protein. The aim of our study was to investigate the effects of antimalarial drugs on human recombinant glutathione S-transferase (GSTs) activity in the context of searching for effective and clinically acceptable inhibitors of these enzymes. Human recombinant GSTs heterologously expressed in Escherichia coli were used for inhibition studies. GST Al-l activity was inhibited by artemisinin with an IC,, of 6 pM, whilst GST MI-l was inhibited by quinidine and its diastereoisomer quinine with IC5,s of I2 pM and 17 pM, respectively. GST M3-3 was inhibited by tetracycline only with an IC,, of 47 pM. GST PI-l was the most susceptible enzyme to inhibition by antimalarials with IC,, values of I, 2, 1, 4, and 13 pM for pyrimethamine, arteniislnin, quinidine, quinine and tetracycline, respectively. The IC,, values obtained for artemisinin, quinine, quinidine and tetracycline are below peak plasma concentrations obtained during therapy of malaria with these drugs. It seems likely, therefore, that GSTs may be inhibited in vivo at doses normally used in clinical practice. Using the substrate ethacrynic acid, a diuretic drug also used as a modulator to overcome drug resistance in tumour cells, GST PI-l activity was inhibited by tetracycline, quinine, pyrimethamine and quinidine with IC,, values of 18, 27, 45 and 70 pM, respectively. The ubiquitous expression of GSTs in different malignancies suggests that the addition of nontoxic reversing agents such as antimalarials could enhance the efficacy of a variety of alkylating agents.
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    Phenotyping of the glutathione S-transferase M1 polymorphism in Zimbabweans and the effects of chloroquine on blood glutathione S-transferases M1-A
    (Elsevier, 1997-05-31) Mukanganyama, Stanley; Masimirembwa, Collen M.; Naik, Yogeshkumar S.; Hasler, Julia A.
    The frequency of the null allele phenotype of glutathione S-transferase (GST) M1 was investigated in 114 Zimbabweans and results for a subset of 63 subjects were compared with genotyping by PCR. In addition, the effect of the antimalarial chloroquine on blood levels of GSTMl and GSTA in 19 subjects was studied. Quantification of GSTs was by enzyme linked immunosorbent assays (ELISA). Thirty percent of the subjects were of the GSTMl null phenotype. Comparison of results of phenotyping by ELISA and genotyping by PCR showed that 16% of samples were in discordance; unknown mutations in the GSTMl gene in the Zimbabwean population may explain this observation. Chloroquine decreased levels of blood GSTM1 and GSTA by 50% or more. In populations treated with chloroquine, these decreases in GST activities might lead to compromised ability to detoxify xenobiotics, could confound GSTMl phenotyping and might invalidate use of GSTA as an indicator of liver damage. O 1997 Elsevier Science B.V. Keywords: Glutathione S-transferases; Phenotype; Black Zimbabweans; Chloroquine