Quantitative differences in the active-site hydrophobicity of five human glutathione S-transferase isoenzymes:: Water-soluble carcinogen-selective properties of the neoplastic GSTP1-1 species

The active-site (the H-site) hydrophobicity of five human glutathione S-transferases (GSTs) was analyzed by application of linear free energy relationships (LFERs) with a series of S-alkylated glutathione inhibitors, GS(CH2)(n - 1)CH3 (n = 1-14). Distinct linear reltionships were observed in the plots of log K-i (inhibition constant) vs n for the five forms, whereby the K(i)s varied by three to four orders of magnitude. Mean free enthalpy changes per methylene group (-Delta Delta G degrees s), a measure of H-site hydrophobicity, were in the order M1-1 (4.6 kJ/mol) > Al-l (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. (C) 1999 Academic Press.