Interactions of alpha, beta-unsaturated aldehydes and ketones with human glutathione S-transferase P1-1.

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van Iersel ML, Ploemen JP, Lo Bello M, Federici G, van Bladeren PJ

Interactions of alpha, beta-unsaturated aldehydes and ketones with human glutathione S-transferase P1-1.

Chem Biol Interact. 1997 Dec 12;108(1-2):67-78.

PubMed ID

9463521 [ View in PubMed

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Abstract

In the present study the irreversible inhibition of human glutathione S-transferase P1-1 (GSTP1-1) by alpha, beta-unsaturated aldehydes and ketones was studied. When GSTP1-1 was incubated with a 50-fold molar excess of the aldehydes acrolein (ACR) and 4-hydroxy-2-nonenal (HNE) and the ketones curcumin (CUR) and ethacrynic acid (EA) at 22 degrees C, all of them inactivated GSTP1-1. The remaining activity after 4 h of incubation in all cases was lower than 10%. The aldehydes crotonaldehyde (CRA), cinnamaldehyde (CA) and trans-2-hexenal were found to inhibit GSTP1-1 only at a 5000-fold molar excess and even then, for example, for CA a higher remaining activity of 17% was observed. The same inhibition experiments were conducted with 3 mutants of GSTP1-1: the C47S and C101S mutants and the double mutant C47S/C101S. Remaining activity for C47S varied between +/- 40% for CRA, CA, CUR and HEX and +/- 80% for ACR, EA and HNE. For C101S it varied between 0 and 9% and for the double mutant C47S/C101S, activity after 4 h of incubation was variable. Again it varied between +/- 40% for CRA, CA, CUR and HEX and +/- 80% for ACR, EA and HNE. EA is known to react almost exclusively with cysteine 47. When [14C]EA was incubated with the GSTP1-1, modified by the alpha, beta-unsaturated carbonyl compounds, no [14C]EA was incorporated in the enzyme, indicating that in all cases this cysteine residue was one of the major targets. Since Michael addition with these reagents is known to be reversible, the results of incubation of the inactivated enzymes with an excess of glutathione (GSH) were determined. For all compounds, a restoration of the catalytic activity was observed. The results indicate that alpha, beta-unsaturated carbonyl derivatives inhibit GSTP1-1 irreversibly mainly by binding to cysteine residues of GSTP1-1, especially Cys-47, This means that some of these compounds (e.g. CUR) might modify GST activity in vivo when GSH concentrations are low by covalent binding to the enzyme.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Curcumin	Glutathione S-transferase P	Protein	Humans	Unknown	Not Available	Details
Curcumin sulfate	Glutathione S-transferase P	Protein	Humans	Unknown	Not Available	Details
Etacrynic acid	Glutathione S-transferase P	Protein	Humans	Unknown	Inhibitor	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Etacrynic acid	Glutathione S-transferase A2	Protein	Humans	Unknown	Inhibitor	Details