Many of the physiological and biochemical determinants of chemically induced target-organ toxicity are poorly understood. It has recently been demonstrated that glutathione (GSH) conjugation with xenobiotics can result in the formation of reactive intermediates and the kidney appears particularly susceptible to the toxic effects of these conjugates. We have recently shown that 2-bromohydroquinone (2-BHQ) gives rise to a mixture of isomeric mono- and di-substituted GSH conjugates, the latter being a potent nephrotoxin. This is the first example of aromatic conjugation with GSH resulting in increased toxicity. GSH conjugation to redox cycling quinones may be a common pathway of toxicity of such compounds and this possibility warrants further investigation. The first step in the metabolism and membrane transport of GSH and its conjugates involves hydrolysis by gamma-glutamyl transpeptidase (GGT) and the differential toxicity exhibited by the mono- and di-substituted 2- BHQ-GSH conjugates appears to be a consequence of the more extensive GGT mediated renal uptake of the di-GSyl adduct. In this respect, the addition of GSH to quinones might subsequently result in their preferential uptake into cells rich in GGT. Thus, in addition to the kidney, tissues such as the pancreas, spleen and seminal vesicles might be found particularly susceptible to the toxic effects of these conjugates. GSH might therefore act as a carrier of redox cycling compounds through the body in which the initial detoxification can be followed by release of the reactive compound at some other site. It is well known that neoplastic cells contain elevated levels of GGT. These high concentrations of GGT in tumors, in addition to its specific localization within the brush border membrane of renal proximal tubule cells, has stimulated interest in the potential that this enzyme might be exploited for the site-specific delivery of drugs. If the renal toxicity of GSH-linked quinones could be circumvented then such agents might prove useful directed against GGT in neoplastic cells. In this respect, pre-neoplastic liver nodules might be good targets for these compounds since normal liver contains negligible GGT and 2-BHQ-GSH has no apparent effect on liver pathology. In contrast to 2-BHQ, 4-bromocatechol (4-BC), which also forms a GSH conjugate, is not nephrotoxic. The reason for this difference is unclear but may be related to either decreased cellular uptake (via GGT) or decreased intracellular activation. In contrast to the oxidation of hydroquinones, catechols (o-diphenols) are substrates for the enzyme tyrosinase. The o-quinone linked GSH conjugates might thus be preferentially toxic to cells containing both GGT and tyrosinase whereas p-quinone hydroquinone) linked GSH conjugates would be preferentially toxic to cells containing both GGT and a corresponding """"""""hydroquinone oxidase"""""""". We therefore also propose to investigate the relative cell specific cytotoxicity of o-quinol and p-quinol linked GSH conjugates.
| Cohen, Jennifer D; Tham, Kimberly Y; Mastrandrea, Nicholas J et al. (2011) cAMP-dependent cytosolic mislocalization of p27(kip)-cyclin D1 during quinol-thioether-induced tuberous sclerosis renal cell carcinoma. Toxicol Sci 122:361-71 |
| Cohen, Jennifer D; Gard, Jaime M C; Nagle, Raymond B et al. (2011) ERK crosstalks with 4EBP1 to activate cyclin D1 translation during quinol-thioether-induced tuberous sclerosis renal cell carcinoma. Toxicol Sci 124:75-87 |
