MODULATION &MECHANISMS OF SULFUR CONJUGATE MEDIATE

The mechanisms by which various chemicals cause nephrotoxicity
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.
GSH dependent metabolic activation within the kidney probably
has greater toxicological significance than that mediated by the
cytochrome P-450 dependent mono-oxygenases. This is because
of the relatively low activity of renal P-450, the high activity of
GSH related enzymes and the rapid turnover of GSH within the
kidney. However little is known of the metabolic and pathologic
mechanisms by which GSH and cysteine conjugates elicit
nephrotoxicity nor of those factors which regulate the generation
of potentially reactive thiols from GSH/cysteine conjugates. 2-
Bromohydroquinone (2-BHQ) gives rise to a mixture of isomeric
mono- and disubstituted GSH conjugates, the latter being a potent
nephrotoxin. This is the first example of GSH conjugation, to an
aromatic substrate leading to toxicity. GSH conjugation to redox
cycling quinones may be a common pathway of toxicity of such
compounds. We have established in culture three kidney cell lines
of different physiological, morphological and biochemical
properties which provide an ideal model with which to study the
mechanism of GSH-conjugate mediated nephrotoxicity. The cell
lines (i) express widely varying gamma-glutamyl transpeptidase
activitives which enable an ideal means of investigating the role
of this enzyme in GSH conjugate mediated toxicity (ii) are derived
from different anatomical portions of the kidney and thereby
provide a model for determining the role of renal transport
mechanisms in GSH conjugate mediated toxicity and (iii) likely
exhibit differences in prostaglandin synthase activity with which
to probe the role of this enzyme in 2-BHQ activation. Moreover,
the structure of these 2-BHQ-GSH conjugates and their
differential nephrotoxicity provide an ideal model with which to
investigate the mechanism and regulation of GSH conjugate
mediated nephrotoxicity. The relative contribution of tissue
alkylation (via thiol activation) and the redox cycling of the
quinone moiety to toxicity can be determined with these
conjugates.