The interaction of selected natural products with human recombinant glutathione transferases.
The interaction of geshoidin, diospyrin and ergothioneine, with heterologously expressed human glutathione transferases (GSTs) was investigated in vitro. Diospyrin and geshoidin inhibited the three GST isoforms tested, with IC50 values in the range 0.1-0.5 microm, whereas ergothioneine had no effect on the GSTs. The predominant mode of inhibition was noncompetitive with respect to both glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB). Diospyrin, however, competitively inhibited A1-1 and M1-1 with respect to GSH and geshoidin displayed mixed inhibition toward A1-1 with respect to GSH. The Ki values for diospyrin with respect to both GSH and CDNB were in the range 0.08-0.6 microM and those for geshoidin were in the range 16-173 microM. These results indicate that diospyrin is a potent inhibitor of heterologously expressed human GSTs A1-1, M1-1 and P1-1. Diospyrin and geshoidin were also found to inactivate P1-1 with diospyrin being a potent inactivator. Given these inhibitory properties, diospyrin may be a potential GST chemomodulator. Ergothioneine inactivated P1-1 only after preincubation and it enhanced ethacrynic acid inactivation of P1-1. Inactivation of P1-1 by ergothioneine may have implications for the antioxidant roles of P1-1 and ergothioneine in vivo.
Hayeshi
Rose
R
Department of Biochemistry, University of Zimbabwe, Harare, Zimbabwe.
Mukanganyama
Stanley
S
Hazra
Banasri
B
Abegaz
Berhanu
B
Hasler
Julia
J
D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004880:Ergothioneine / Q000494:pharmacology; D005960:Glucosides / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D009281:Naphthalenes / Q000494:pharmacology*; D009285:Naphthoquinones / Q000494:pharmacology; D008517:Phytotherapy; D010946:Plants, Medicinal
D004791:Enzyme Inhibitors; D005960:Glucosides; D009281:Naphthalenes; D009285:Naphthoquinones; C496655:geshoidin; D004880:Ergothioneine; D005982:Glutathione Transferase; C043546:diospyrin