In Vitro Inhibition of Mammalian Glutathione Transferases by Selected Nitrobenzenes

Abstract

Five structurally related nitrobenzenes (1,2-dinitrobenzene, 1,3-dinitrobenzene, 1,4-dinitrobenzene, 1,3,5-trinitrobenzene, and picric acid) and Meisenheimer complex [1-(S-glutathionyl)-2,4,6-trinitrocyclohexadienate] were evaluated as possible inhibitors of af nity puri ed mammalian glutathione transferases (GSTs) isolated from human liver or human term placenta and rat liver. The results suggest that the degree of GST inhibition depends upon both the chemical in question and the enzyme source. Among the nitrobenzenes tested, 1,3,5-trinitrobenzene (TNB) was found to be the most potent inhibitor of GST activity toward 1-chloro-2,4-dinitrobenzene (CDNB) from all the sources, whereas 1,3-dinitrobenzene (1,3-DNB) was the least effective. TNB-caused inhibition of GST activity toward CDNB appeared to be isozyme speci c in that compared to the enzyme from human term placenta (GSTP1-1), the degree of inhibition of the mixture of GST isozymes present in the livers of adult rats and humans was low. The enzyme assays conducted with 3,4-dichloro-1-nitrobenzene (DCNB), ethacrynic acid (EA), and 4-nitropyridine N-oxide also suggested the isozymespeci c inhibition of rat liver GST activity by TNB. The nature of TNB-caused inhibition of GSTP1-1 was competitive with respect to CDNB and yielded a K i value of 12.5 µ M. With EA, a speci c substrate for GSTP1-1, an IC 50 value of » 16 µ M was estimated for the GSTP1-1 inhibition by TNB. The Meisenheimer complex, the product of nonenzymatic GSH conjugation with TNB by different GSTs, was found to be the most potent inhibitor of mammalian GSTs, and IC 50 values ranged between 1 and 4 µ M when the enzyme activity was assayed using CDNB. The nature of GSTP1-1 inhibition was noncompetitive with respect to CDNB, with a K i value of 1 µ M for Meisenheimer complex. Although a precise mechanism was not identi ed, it is postulated that GSH depletion and/or GST inhibition may contribute, at least partly, to the target organ toxicity caused by exposures of animals to different nitrobenzenes reported in the literature.

The para isomer of dinitrobenzene disrupts redox homeostasis in liver and kidney of male wistar rats

“…One of the mechanisms of p -DNB is their ability to generate free radicals and trigger oxidative stress in vivo [28] . In Nigeria, the increasing use of dynamite, plastics, dyes, petrochemicals products and improperly managed waste products from manufacturing plants may contribute to p -DNB toxicity and possibly introduce high concentrations of this potential hepatorenal toxicant into the environment.…”

Nitrobenzene toxicity: QSAR correlations and mechanistic interpretations

“…Nitroaromatics are hazardous chemicals that display several manifestations of toxicity, including skin sensitization, 1 immunotoxicity, 2 germ cell degeneration, 3 inhibition of liver enzymes 4 and also a conjectured carcinogenicity. 5 Nitrobenzene toxicity to the aquatic ciliate Tetrahymena pyriformis has been extensively studied by several groups of workers 1,[6][7][8] with the use of 2D and 3D QSAR methodologies.…”

Design and Biological Evaluation of 2,2′-Dinitrodiphenylmethane Derivatives

“…The chemistry of 2,2′-dinitrodiphenylmethane compounds had been investigated extensively for the last several decades leading to new synthetic routes, variety of structures and their potential biological applications [1][2][3][4] . Nitroaromatics are hazardous chemicals that display several manifestations of toxicity, including skin sensitization 5 , immunotoxicity 6 , germ cell degeneration 7 , inhibition of liver enzymes 8 and also a conjectured carcinogenicity 9 . Nitro aromatic compounds are cytotoxic, it has been proposed that their cytotoxicity is due to the generation of reactive oxygen species such as superoxide radical anion, singlet oxygen and hydrogen peroxide 10 .…”