title: Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist.
abstract: Acetaminophen (APAP) induced increases in intrahepatic expression of interleukin (IL)-1 alpha, IL-1 beta, and IL-1 receptor antagonist (IL-1ra), when administered intraperitoneally. These observations prompted us to define the pathophysiological roles of IL-1ra in APAP-induced liver injury. Compared with wild-type (WT) mouse-derived hepatocytes, IL-1ra-deficient (IL-1ra KO)-derived hepatocytes exhibited more resistance against APAP but not APAP-derived major toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Moreover, the amounts of a major APAP adduct (selenium-binding protein), an indicator of NAPQI generation from APAP, was significantly lower in IL-1ra KO mice than WT mice with depressed intrahepatic expression of CYP1A2, CYP2E1, and CYP3A11, the enzymes crucially involved in NAPQI generation from APAP. These observations would indicate that IL-1ra deficiency impaired APAP metabolism. IL-1 alpha and IL-1 beta were expressed to similar extents in livers of untreated IL-1ra KO and WT mice. By contrast, the intranuclear amount of p65 of NF-kappaB, which can suppress the gene expression of CYP1A2, CYP2E1, and CYP3A11, was higher in untreated IL-1ra KO than WT mice. Moreover, when mice were intraperitoneally administered APAP (200 mg/kg), IL-1ra KO mice exhibited attenuated APAP-induced liver injury as evidenced by reductions in serum alanine transferase levels and histopathological changes such as centrilobular necrosis, hemorrhages, and leukocyte infiltration. Finally, when given 12 h before APAP challenge, IL-1 alpha repressed the intrahepatic expression of CYP1A2, CYP2E1, and CYP3A11, eventually reducing APAP-induced liver injury, along with reduction in APAP adducts. Collectively, NF-kappaB was activated without any stimuli by the genetic disruption of IL-1ra, and suppressed cytochrome P450 enzyme expression, thereby reducing APAP-induced liver injury.
authors.affiliation: Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Ishibe
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kimura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishida
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Takayasu
authors.forename: Takahito
authors.initials: T
authors.lastname: Hayashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Ikuhiro
authors.initials: I
authors.lastname: Sakata
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kondo
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology / Q000506:poisoning; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology / Q000506:poisoning; D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000494:pharmacology; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D016328:NF-kappa B; D051996:Transcription Factor RelA; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2