Print Email Facebook Twitter Regioselectivity and quantitative structure - Activity relationships for the conjugation of a series of fluoronitrobenzenes by purified glutathione S-transferase enzymes from rat and man Title Regioselectivity and quantitative structure - Activity relationships for the conjugation of a series of fluoronitrobenzenes by purified glutathione S-transferase enzymes from rat and man Author Soffers, A.E.M.F. Ploemen, J.H.T.M. Moonen, M.J.H. Wobbes, T. van Ommen, B. Vervoort, J. van Bladeren, P.J. Rietjens, I.M.C.M. Instituut CIVO-Toxicologie en Voeding TNO Publication year 1996 Abstract Quantitative structure - activity relationships (QSAR's) are described for the rate of conjugation of a series of fluoronitrobenzenes with cytosolic 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, and 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 electrophilic attack (i.e., E(LUMO)) and the calculated relative heat of formation for formation of the respective Meisenheimer complex intermediate (ΔΔHF). In addition, the regioselectivity of the reaction was determined and compared. The results obtained strongly support the conclusion that chemical reactivity of the fluoronitrobenzenes is the main factor determining the outcomes of their conversion by all glutathione S-transferase enzymes. The regioselectivities vary only a few percent from one enzyme to another, whereas QSAR lines for all purified enzymes 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 complex, is the rate-limiting step in the overall catalysis. The fact that chemical reactivity of the fluoronitrobenzenes is the main factor in setting the outcomes of the overall conversion by the different glutathione S-transferase enzymes implies that extrapolation from rat to results of other species including man, and also from one individual to another, must be feasible. That this is actually the case is clearly demonstrated by the results of the present study. Chemicals/CAS: Fluorobenzenes; Glutathione Transferase, EC 188.8.131.52; Glutathione, 70-18-8; Monoamine Oxidase Inhibitors Subject AgedAnimalsBiotransformationChromatography, High Pressure LiquidCytosolFemaleFluorobenzenesGlutathioneGlutathione TransferaseHumansKineticsLiverMagnetic Resonance SpectroscopyMaleMolecular ConformationMonoamine Oxidase InhibitorsRatsRats, WistarStructure-Activity RelationshipSubstrate SpecificityAnimalia To reference this document use: http://resolver.tudelft.nl/uuid:93bf584d-0935-49d0-bca7-e0c2af799de4 TNO identifier 233278 ISSN 0893-228X Source Chemical Research in Toxicology, 9 (3), 638-646 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.