REGIOSELECTIVITY AND QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS FOR THE CONJUGATION OF A SERIES OF FLUORONITROBENZENES BY PURIFIED GLUTATHIONE-S-TRANSFERASE ENZYMES FROM RAT AND MAN

Quantitative structure-activity relationships (QSAR's) are described f or the rate of conjugation of a series of fluoronitrobenzenes with cyt osolic as well as with two major alpha and mu class enzymes of rat and human liver, viz., glutathione S-transferases (GST) 1-1, 3-3, A1-1, a nd M1a-1a. For all purified enzymes studied, the natural logarithm of the rate of conversion of the fluoronitrobenzenes correlates with both the calculated reactivity of the fluoronitrobenzenes for an electroph ilic attack (i.e., E(LUMO)) and the calculated relative heat of format ion for formation of the respective Meisenheimer complex intermediate (Delta Delta HF). In addition, the regioselectivity of the reaction wa s determined and compared. The results obtained strongly support the c onclusion that chemical reactivity of the fluoronitrobenzenes is the m ain factor determining the outcomes of their conversion by all glutath ione S-transferase enzymes, The regioselectivities vary only a few per cent from one enzyme to another, whereas QSAR lines for all purified e nzymes are in the same region and run parallel. This indicates that in the overall reaction the nucleophilic attack of the thiolate anion on the fluoronitrobenzenes, leading to formation of the Meisenheimer com plex, is the rate-limiting step in the overall catalysis. The fact tha t chemical reactivity of the fluoronitrobenzenes is the main factor in setting the outcomes of the overall conversion by the different gluta thione S-transferase enzymes implies that extrapolation from rat to re sults of other species including man, and also from one individual to another, must be feasible. That this is actually the case is clearly d emonstrated by the results of the present study.