title: Inhibition of human glutathione transferases by dinitronaphthalene derivatives.
abstract: Glutathione transferase (GST) enzymes catalyze the conjugation of glutathione with reactive functional groups of endogenous compounds and xenobiotics, including halonitroaromatics. 1-Chloro-2,4-dinitrobenzene (CDNB) is one of the most commonly used substrates for GST activity assays. We have studied the interactions of dinitronaphthalene analogues of CDNB with recombinant human GST enzymes (Alpha, Mu, and Pi classes) expressed in Escherichia coli. Dinitronaphthalene derivatives were found to be GST inhibitors. The highest potency of inhibition was observed towards Mu-class GSTs, M1-1 and M2-2; IC50 values for 1-methoxy- and 1-ethoxy-2,4-dinitronaphthalene were in the high nanomolar to low micromolar range. Inhibition accompanies the formation, at the enzyme active site, of very stable Meisenheimer complex intermediates.
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Hilary
authors.initials: H
authors.lastname: Groom
authors.affiliation: Department of Chemistry, Hope College, Holland, MI 49423, United States.
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Hope College, Holland, MI 49423, United States.
authors.forename: Pravin
authors.initials: P
authors.lastname: Patil
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada. Electronic address: djosephy@uoguelph.ca.
authors.forename: P David
authors.initials: PD
authors.lastname: Josephy
mesh_terms: D020134:Catalytic Domain; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry*; D009574:Nitro Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D009281:Naphthalenes; D009574:Nitro Compounds; D011994:Recombinant Proteins; D005982:Glutathione Transferase
keywords: 1-Chloro-2,4-dinitronaphthalene; Glutathione transferase; Meisenheimer complex