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Vol. 289, Issue 1, 580-586, April 1999
University of Kansas Medical Center, Kansas City, Kansas (J.L.,
Y.L., D.H., and C.D.K.) and
University of Connecticut, Storrs,
Connecticut (S.E.S.-J., A.L., and S.D.C.)
The purpose of this study was to examine whether intracellular
metallothionein (MT) protects against acetaminophen hepatotoxicity. MT-I/II knockout (MT-null) and control mice were given acetaminophen (150-500 mg/kg i.p.), and liver injury was assessed 24 h later. MT-null mice were more susceptible than controls to
acetaminophen-induced lethality and hepatotoxicity, as evidenced by
elevated serum enzyme activities and histopathology. Zinc pretreatment,
a method of MT induction, protected against acetaminophen
hepatotoxicity in control mice, but not in MT-null mice. The
susceptibility of MT-null mice to acetaminophen hepatotoxicity was not
due to the increased acetaminophen bioactivation, as cytochrome P-450
enzymes, and acetaminophen-reactive metabolites in bile and urine were
not increased in MT-null mice. Western blots of liver cytosol indicated that acetaminophen covalent binding at 4 h increased with
acetaminophen dose, but there was no consistent difference between
control and MT-null mice. Acetaminophen injection depleted cellular
glutathione similarly in both control and MT-null mice, but produced
more lipid peroxidation in MT-null mice, as evidenced by the abundance of thiobarbiturate-reactive substances, and by immunohistochemical localization of 4-hydroxynonenal and malondialdehyde protein adducts. MT-null hepatocytes were more susceptible than control cells to oxidative stress and cytotoxicity produced by
N-acetylbenzoquinoneimine, a reactive metabolite of
acetaminophen, as determined by oxidation of 2',7'-dichlorofluorescin
diacetate and lactate dehydrogenase leakage. In summary, this study
demonstrated that MT deficiency renders animals more vulnerable to
acetaminophen-induced hepatotoxicity. The increased sensitivity does
not appear to be due to increased acetaminophen activation, glutathione
depletion, or covalent binding, but appears to be associated with the
antioxidant role of MT.
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