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College of Pharmacy, Previous studies have shown that radiation in combination with oltipraz
enhances hepatic microsomal epoxide hydrolase expression. The effects
of 
-ray radiation exposure in combination with oltipraz on the
expression of hepatic glutathione-S-transferase (GST)
subunits Ya, Yb1, Yb2,
Yc1, and Yc2 were examined in the rat.
Northern RNA blot analyses revealed that GST mRNA levels were altered
in response to daily 3- or 0.5-Gy doses of radiation. The hepatic GST
mRNA levels were transiently decreased at 3 and 8 hr after a single
3-Gy dose of radiation. The GST Ya, Yb1, Yb2, Yc1, and Yc2 mRNA levels
were increased by 2-4-fold at 15 and 24 hr after irradiation with 3 Gy, followed by return to the levels of untreated rats at 48 hr after
treatment. The treatment of animals with oltipraz alone resulted in
dose-related increases in the GST Ya, Yb1, Yc1, and Yc2 mRNA levels,
whereas Yb2 mRNA levels were minimally increased. Although a single
dose of oltipraz (30 mg/kg orally) caused a minimal 2-fold elevation in
the hepatic GST Ya mRNA level, exposure of animals to both oltipraz and
3-Gy radiation resulted in a 4-fold relative increase in GST Ya mRNA
level, indicating that the Ya mRNA expression was additively enhanced
by the combination treatment. The Yb1/2 and Yc1/2 mRNA expressions were
also enhanced by oltipraz in combination with radiation. Multiple
exposure of rats to daily 0.5-Gy radiation caused time-related
increases in GST gene expression. The greatest enhancement in GST
expression was observed at 24 hr after a single 0.5-Gy dose of
radiation in conjunction with oltipraz (e.g., a 9-fold relative
increase in GST Ya), whereas the relative additive
increases in GST mRNA were less pronounced at day 3 or 5 after
treatment. These increases in the GST mRNA levels were consistent with
those in the immunochemically detectable GST protein levels.
Histopathological examinations revealed that exposure of rats to
radiation (0.5 Gy/day for 3-5 days) caused mild-to-moderate hepatocyte
degeneration with sinusoidal congestion, whereas oltipraz (30 mg/kg/day
for 3 days) was effective in blocking the radiation-induced liver
injury. The enhanced expression of these GST isoforms by oltipraz may
be associated in part with its hepatoprotective effect against the
injury caused by ionizing radiation.
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
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