The importance of
epoxide hydrolase in preventing
styrene 7,8-oxide-induced hepatoxicity was studied in isolated perfused rat livers depleted of GSH. GSH depletion was accomplished by treating the rats with
diethyl maleate 45 min before surgical removal of their livers.
Diethyl maleate itself caused mild hepatotoxicity that was observed histologically and measured biochemically by the release of hepatic
transaminase enzymes into the circulation. GSH
transferase activity was decreased in perfused livers from
diethyl maleate-treated rats as shown by the persistence of circulating
styrene oxide compared with that seen in experiments with livers from control animals. In the absence of GSH
transferase activity, the rate of
styrene oxide biotransformation by
epoxide hydrolase was sufficient to prevent measurable hepatotoxicity, up to
epoxide concentrations tolerated by livers from control rats. The administration of 500 mumol of
styrene oxide to perfused livers from
diethyl maleate-treated rats caused periportal
necrosis and extensive covalent binding of
styrene oxide-derived radioactivity to tissue
protein. These effects, however, were no more severe than those seen in perfused livers from control animals given 500 mumol of
styrene oxide. Due to high GSH
transferase activity in perfused livers from untreated rats, the capacity of
epoxide hydrolase to detoxify
styrene oxide is difficult to measure in this system. The detoxication potential of
epoxide hydrolase was clearly demonstrated in this study with GSH-depleted liver preparations.