Alpha,beta-unsaturated carbonyl compounds: inhibition of rat liver glutathione S-transferase isozymes and chemical reaction with reduced glutathione.

Five different alpha,beta-unsaturated carbonyl compounds displayed different reactivities with regard to inhibition of alpha- and mu-class isozymes of rat liver glutathione S-transferases and the chemical reaction with glutathione. Only (E)-2-octenal and (E)-3-nonen-2-one exhibited significant levels of inhibition for each of the rat liver GST isozymes examined. The (E)-2-octenal was more effective as an inhibitor of the alpha-class of isozymes when compared to the mu-class, whereas the (E)-3-nonen-2-one showed a greater degree of inhibition of the mu-class of isozymes relative to the alpha-class. Isozyme 1-1 demonstrated the greatest degree of inhibition with (E)-2-octenal (IC50 = 5.89 microM) of all inhibitor/isozyme combinations. The Ki values for (E)-2-octenal and (E)-3-nonen-2-one toward selected alpha- and mu-class of rat liver glutathione S-transferase isozymes were determined and both of these compounds competitively inhibited all five of the rat liver glutathione S-transferase isozymes examined. The Ki values obtained for these two compounds were significantly different for each of the isozymes except for isozyme 4-4. With the alpha-class of rat liver GST isozymes, (E)-3-nonen-2-one showed a larger Ki value than (E)-2-octenal. Whereas, with the mu-class, (E)-2-octenal exhibited a larger Ki value than (E)-3-nonen-2-one. The rate constants of the forward reaction (k+1), as well as the equilibrium constants (Kd) were determined and the rate constants of the reverse reaction (k-1) were calculated.