Modulation of Quinol/Quinone-Thioether Toxicity by Intramolecular Detoxication

Abstract

A variety of cytotoxic, mutagenic, and carcinogenic conjugates of GSH require processing by enzymes of the mercapturic acid pathway to produce toxicity. However, metabolism of quinone-thioethers by gamma-GT can result in either activation or detoxication. For example, inhibition of gamma-GT completely protects against the nephrotoxicity caused by 2-bromo-bis-(glutathion-S-yl)hydroquinone and 2,3,5-tris-(glutathion-S-ly)hydroquinone, whereas the same protocol potentiates the nephrotoxicity of 2,5-dichloro-3-(glutathion-S-yl)hydroquinone and 2,5,6-trichloro-3-(glutathion-S-yl)hydroquinone. Which of these two scenarios occur as a consequence of metabolism by gamma-GT appears to be determined by the relative rate at which the product is transported into cells and/or interacts with cellular constituents, and the rate which the product undergoes intramolecular detoxication (cyclization) to a 1,4-benzothiazine. The same reaction may also explain why the mercapturic acid metabolite of menadione is nephrotoxic following systemic administration, whereas the GSH conjugate is without activity. Species differences exist in susceptibility to both 2-bromo-bis-(glutathion-S-ly)hydroquinone and 2,3,5-tris(glutathion-S-ly)hydroquinone induced nephrotoxicity. In this case, however, susceptibility does not correlate with renal gamma-GT activity, but rather to differences in the rate at which the corresponding cysteine and N-acetylcysteine conjugates undergo N-acetylation/N-deacetylation cycling. Thus the guinea pig--which is the only other rodent species (in addition to the rat), that is susceptible to 2-bromo-bis-(glutathion-S-ly)hydroquinone and 2,3,5-tris-(glutathion-S-ly)hydroquinone mediated nephrotoxicity--expresses the lowest activity of renal gamma-GT but exhibits the highest N-deacetylation:N-acetylation ratio. Differences in kinetics of these two reactions therefore contribute to species susceptibility. The toxicity of quinol/quinone thioethers is dependent upon a number of physiological, biochemical, and electrochemical factors. The rates at which quinol-thioethers undergo oxidation, with the concomitant generation of reactive oxygen species (IV, Fig. 1), macromolecular arylation (V, Fig. 1), intramolecular cyclization (VI, Fig. 1), and acetylation-deacetylation cycling (III, Fig. 1) is dependent upon the substrate in question. All these factors will contribute to the cell, tissue, and species susceptibility of this interesting class of GSH conjugates.