Quantitative Differences in the Active-Site Hydrophobicity of Five Human GlutathioneS-Transferase Isoenzymes: Water-Soluble Carcinogen-Selective Properties of the Neoplastic GSTP1-1 Species

Abstract

The active-site (the H-site) hydrophobicity of five human glutathioneS-transferases (GSTs) was analyzed by application of linear free energy relationships (LFERs) with a series of S-alkylated glutathione inhibitors, GS(CH2)n− 1CH3(n= 1–14). Distinct linear reltionships were observed in the plots of logKi(inhibition constant) vsnfor the five forms, whereby theKis varied by three to four orders of magnitude. Mean free enthalpy changes per methylene group (−ΔΔG°s), a measure of H-site hydrophobicity, were in the order M1-1 (4.6 kJ/mol) > A1-1 (3.9 kJ/mol) > A1-2 (3.8 kJ/mol) > A2-2 (2.8 kJ/mol) > P1-1 (1.6 kJ/mol). The quantitative differences may in part account for the extraordinary broad and overlapping substrate specificities of the Alpha-, Mu-, and Pi-class isoenzymes. In contrast to the Alpha and Mu classes being selective for strongly electrophilic compounds, the neoplastic P1-1 species was indicated to be selective for weakly electrophilic and water-soluble carcinogens such as acrolein and hydroxyalkenals.