WEAK ELECTROPHILE SELECTIVE CHARACTERISTICS OF THE RAT PRENEOPLASTIC MARKER ENZYME GLUTATHIONE-S-TRANSFERASE P-FORM, GST-P(7-7) - A THEORY OF LINEAR FREE-ENERGY RELATIONSHIPS FOR EVALUATION OF THE ACTIVE-SITE HYDROPHOBICITY OF ISOENZYMES

Subsite (the H-site) hydrophobicity of the rat glutathione S-transfera se P-form (GST-P, 7-7, pi class species) and six other GST species of the alpha and mu classes was examined theoretically and experimentally by application of linear free energy relationships (LFERs) with a ser ies of S-alkylated glutathiones, GS(CH2)(n-1)CH3 (n = 1-12), Plots of log Ki (inhibition constant) versus rt were used to generate LFERs for microscopic hydrophobic interactions. The free enthalpic change per m ethylene group (-Delta Delta G degrees, absolute value) evaluated for GST-P (1.8 kJ/mol) was lower than those for the other six forms (2.4-3 .5 kJ/mol), In addition, the enthalpic change (Delta Delta H degrees) determined from van't Hoff plots was much smaller for GST-P (0.5 kJ/mo l) than the GST1-1 value (5.9 kJ/mol). As these thermodynamic paramete rs, Delta Delta G degrees and Delta Delta H degrees, may be considered as indirect and direct measures of GST hydrophobicity respectively, t he II-site hydrophobicity of GST-P is thus very low as compared with t hose of other forms, clearly indicating that the pi class GST-P select ively targets for weak electrophiles, i.e. water-soluble carcinogens s uch as acrolein and hydroxy-alkenals, The finding also defines a host- defensive role of the preneoplastic cells against the carcinogenic ins ult, although paradoxical.