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Inhibition of glutathione S-transferase activity in human melanoma cells by alfa, beta-unsaturated carbonyl derivatives : effects of acrolein, cinnamaldehyde, citral, crotonaldehyde, curcumin, ethacrynic acid, and trans-2-hexenal

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Author: Iersel, M.L.P.S. van · Ploemen, J.P.H.T.M. · Struik, I. · Amersfoort, C. van · Keyzer, A.E. · Schefferlie, J.G. · Bladeren, P.J. van
Institution: TNO Voeding
Source:Chemico-Biological Interactions, 2, 102, 117-132
Identifier: 68910
doi: doi:10.1016/S0009-2797(96)03739-8
Keywords: Health · Cells · Glutathione S-transferases · Inhibition · Ketones · 2 hexenal · Cinnamaldehyde · Citral · Crotonaldehyde · Controlled study · Enzyme activity · Enzyme inhibition · High performance liquid chromatography · Human · Human cell · Melanoma cell · Acrolein · Aldehydes · Chromatography, High Pressure Liquid · Curcumin · Enzyme Inhibitors · Ethacrynic Acid · Glutathione · Glutathione Transferase · Humans · Melanoma · Monoterpenes · Skin Neoplasms · Terpenes · Tumor Cells, Cultured


The glutathione S-transferase (GST) activity towards 1-chloro-2,4-dinitrobenzene in intact human IGR-39 melanoma cells was determined by the quantification by HPLC-analysis of the excreted glutathione (GSH) conjugate (S-(2,4-dinitrophenyl)glutathione; DNPSG). The major GST subunit expressed in these melanoma cells is the π-class GST subunit P1. Using this system, the effect of exposure for 1 h to a series of α,β-unsaturated carbonyl compounds at non-toxic concentrations was studied. Curcumin was the most potent inhibitor (96% inhibition at 25 μM), while 67 and 61% inhibition at 25 μM was observed for ethacrynic acid and trans-2-hexenal, respectively. Moderate inhibition was observed for cinnamaldehyde and crotonaldehyde, while no inhibition was found for citral. The reactive acrolein did not inhibit the DNPSG-excretion at 2.5 μM, the highest non-toxic concentration. Up to about 50% GSH-depletion was found after treatment with crotonaldehyde, curcumin and ethacrynic acid, however the consequences for GST conjugation are presumably small. Reversible inhibition of GST was the major mechanism of inhibition of DNPSG-excretion in melanoma cells, except in the cases of curcumin and ethacrynic acid, which compounds also inactivated GSTP1-1 by covalent modification. This was clear from the fact that depending on the dose between 30 and 80% inhibition was still observed after lysis of the cells, under which conditions reversible inhibition is absent. Intracellular levels of DNPSG remained relatively high in the case of ethacrynic acid. It is possible that ethacrynic acid also inhibits the transport of DNPSG by inhibition of the multidrug resistance-associated protein gene encoding glutathione conjugate export pump (MRP/GS-X pump) in some way.Chemicals/CAS: 2-butenal, 4170-30-3; 2-hexenal, 505-57-7; Acrolein, 107-02-8; Aldehydes; cinnamic aldehyde, 104-55-2; citral, 5392-40-5; Curcumin, 458-37-7; Enzyme Inhibitors; Ethacrynic Acid, 58-54-8; Glutathione Transferase, EC; Glutathione, 70-18-8; Monoterpenes; Terpenes