Publication: The role of prostaglandin E2 in acute acetaminophen hepatotoxicity in mice
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Date
2010
Authors
Ćavar, Ivan ; Kelava, Tomislav ; Vukojevic, Katarina ; Saraga-Babić, Mirna ; Čulo, Filip
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Prostaglandin E2 (PGE2), which is
synthesized by many cell types, has a cytoprotective
effect in the gastrointestinal tract and in several other
tissues and cells. On the other hand, overdose or chronic
use of a high dose of acetaminophen (Paracetamol,
APAP) is a major cause of acute liver failure in the
western world. These observations prompted us to
investigate whether PGE2 plays a role in host defence to
toxic effect of APAP. (CBAT6T6xC57Bl/6)F1 hybrid
mice of both sexes were intoxicated with a single lethal
or high sublethal dose of APAP, which was administered
to animals by oral gavage. Stabile analogue of PGE2,
16,16-dimethyl PGE2 (dmPGE2), or inhibitor of its
production, CAY10526, were given intraperitoneally
(i.p.) 30 minutes before or 2 hours after APAP
administration. The toxicity of APAP was determined by
observing the survival of mice during 48 hours, by
measuring concentration of alanine-aminotransferase
(ALT) in plasma 20-22 hours after APAP administration
and by liver histology. The results have shown that PGE2
exhibits a strong hepatoprotective effect when it is given
to mice either before or after APAP, while CAY10526
demonstrated mainly the opposite effect. Immunohistochemical
or immunofluorescent examinations in the
liver tissue generally support these findings, suggesting
that PGE2 inhibited APAP-induced activation of nuclear
factor kappa B (NF-κB). Similarly, PGE2 down
regulated the activity of inducible nitric oxide synthase
(iNOS), which was up regulated by APAP. Thus, by
these and perhaps by other mechanisms, PGE2
contributes to the defence of the organism to noxious
effects of xenobiotics on the liver.
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