Carcinogenesis, Vol 18, 2393-2401, Copyright © 1997 by Oxford University Press
MM Peters, TW Jones, TJ Monks and SS Lau
Hydroquinone, an intermediate used in the chemical industry and a
metabolite of benzene, is a nephrocarcinogen in the 2-year National
Toxicology Program bioassay in male Fischer 344 rats. Current evidence
suggests that certain chemicals may induce carcinogenesis by a mechanism
involving cytotoxicity, followed by sustained regenerative hyperplasia and
ultimately tumor formation. Glutathione (GSH) conjugates of a variety of
hydroquinones are potent nephrotoxicants, and we now report on the effect
of hydroquinone and 2,3,5-(tris- glutathion-S-yl)hydroquinone, on
site-selective cytotoxicity and cell proliferation in rat kidney. Male
Fischer 344 rats (160-200 g) were treated with hydroquinone (1.8 mmol/kg or
4.5 mmol/kg, p.o.) or 2,3,5- (tris-glutathion-S-yl)hydroquinone (7.5
micromol/kg; 1.2-1.5 micromol/rat, i.v.), and blood urea nitrogen (BUN),
urinary gamma- glutamyl transpeptidase (gamma-GT), alkaline phosphatase
(ALP), glutathione-S-transferase (GST) and glucose were measured as indices
of nephrotoxicity. Hydroquinone (1.8 mmol/kg, p.o.) is nephrotoxic in some
rats, but not others, but cell proliferation (BrDU incorporation) in
proximal tubular cells of the S3M region correlates with the degree of
toxicity in individual rats. At 4.5 mmol/kg, hydroquinone causes
significant increases in the urinary excretion of gamma-GT, ALP and GST.
Pretreatment of rats with acivicin prevents hydroquinone-mediated
nephrotoxicity, indicating that toxicity is dependent on the formation of
metabolites that require processing by gamma-GT. Consistent with this view,
2,3,5-(tris-glutathion-S-yl)hydroquinone, a metabolite of hydroquinone,
causes increases in BUN, urinary gamma-GT and ALP, all of which are maximal
12 h after administration of 2,3,5-(tris-glutathion-S- yl)hydroquinone. In
contrast, the maximal excretion of GST and glucose occurs after 24 h. By 72
h, BUN and glucose concentrations return to control levels, while gamma-GT,
ALP and GST remain slightly elevated. Examination of kidney slices by light
microscopy revealed the presence of tubular necrosis in the S3M segment of
the proximal tubule, extending into the medullary rays. Cell proliferation
rates in this region were 2.4, 6.9, 15.3 and 14.3% after 12, 24, 48 and 72
h, respectively, compared to 0.8-2.4% in vehicle controls. Together with
the metabolic data, the results indicate a role for hydroquinone- thioether
metabolites in hydroquinone toxicity and carcinogenicity.
ARTICLES
Cytotoxicity and cell-proliferation induced by the nephrocarcinogen hydroquinone and its nephrotoxic metabolite 2,3,5-(tris-glutathion-S- yl)hydroquinone
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, 78712, USA.
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