GLUTATHIONE CONJUGATION--MEDIATOR OF ORGAN TOXICITY

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date2/1/8812/31/05

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $261,099.00
  • National Institutes of Health: $119,480.00
  • National Institutes of Health: $239,142.00
  • National Institutes of Health
  • National Institutes of Health: $185,179.00
  • National Institutes of Health
  • National Institutes of Health: $161,821.00
  • National Institutes of Health: $69,445.00
  • National Institutes of Health: $246,555.00
  • National Institutes of Health
  • National Institutes of Health: $186,279.00
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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