prostaglandin-d2 and Chemical-and-Drug-Induced-Liver-Injury

Drug-induced liver injury is a growing concern for pharmaceutical companies and patients because numerous drugs have been linked to hepatotoxicity and it is the most common reason for a drug to be withdrawn. Flutamide rarely causes liver dysfunction in humans, and immune allergic reactions have been suggested in some cases. In this study, we investigated the mechanisms of flutamide-induced liver injury in BALB/c mice. Plasma alanine aminotransferase and aspartate aminotransferase levels were significantly increased 3, 6 and 9 h after flutamide (1500 mg kg⁻¹ , p.o.) administration. The biomarker for oxidative stress was not changed, but Th2-dominant immune-related factors, such as interleukin (IL)-4, IL-5, STAT6 and GATA-binding protein (GATA)-3, were induced in flutamide-administered mice. The pre-administration of monoclonal-IL-4 antibody suppressed the hepatotoxicity of flutamide. In addition, we investigated the effect of 13,14-dihydro-15-keto-PGD₂ (DK-PGD₂; 10 µg per mouse, i.p.) administration on flutamide-induced acute liver injury. Coadministration of DK-PGD₂ and flutamide resulted in a significant increase in alanine aminotransferase and a remarkable increase of macrophage inflammatory protein-2. In conclusion, we demonstrated that flutamide-induced acute liver injury is mediated by Th2-dominant immune responses in mice.

Topics: Androgen Antagonists; Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Antineoplastic Agents, Hormonal; Chemical and Drug Induced Liver Injury; Cytokines; Female; Flutamide; GATA3 Transcription Factor; Gene Expression Regulation; Interleukin-4; Liver; Mice; Mice, Inbred BALB C; Oxidative Stress; Prostaglandin D2; RNA, Messenger; STAT6 Transcription Factor; Th2 Cells

Drug-induced liver injury (DILI) is a major problem in drug development and clinical drug therapy. In most cases, the mechanisms are still unknown. It is difficult to predict DILI in humans due to the lack of experimental animal models. Dicloxacillin, penicillinase-sensitive penicillin, rarely causes cholestatic or mixed liver injury, and there is some evidence for immunoallergic idiosyncratic reaction in human. In this study, we investigated the mechanisms of dicloxacillin-induced liver injury. Plasma ALT and total-bilirubin (T-Bil) levels were significantly increased in dicloxacillin-administered (600 mg/kg, i.p.) mice. Dicloxacillin administration induced Th2 (helper T cells)-mediated factors and increased the plasma interleukin (IL)-4 level. Neutralization of IL-4 suppressed the hepatotoxicity of dicloxacillin, and recombinant mouse IL-4 administration (0.5 or 2.0 μg/mouse, i.p.) exacerbated it. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a cognate receptor for prostaglandin (PG) D(2), and is suggested to be involved in Th2-dependent allergic inflammation. We investigated the effect of 13,14-Dihydro-15-keto-PGD(2) (DK-PGD(2); 10 μg/mouse, i.p.) administration on dicloxacillin-induced liver injury. DK-PGD(2)/dicloxacillin coadministration resulted in a significant increase of alanine aminotransferases and a remarkable increase of macrophage inflammatory protein 2 expression. In conclusion, to the best of our knowledge, this is the first report to demonstrate that dicloxacillin-induced liver injury is mediated by a Th2-type immune reaction and exacerbated by DK-PGD(2).

Topics: Alanine Transaminase; Animals; Anti-Bacterial Agents; Antibodies, Blocking; Bilirubin; Chemical and Drug Induced Liver Injury; Dicloxacillin; Female; Interleukin-4; Liver; Mice; Mice, Inbred BALB C; Prostaglandin D2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; T-Lymphocytes, Helper-Inducer; Th2 Cells

Despite the utility of cyclooxygenase (COX) inhibition as an antiinflammatory strategy, prostaglandin (PG) products of COX-1 and -2 provide important regulatory functions in some pathophysiological states. Scattered reports suggest that COX inhibition may also promote adverse drug events. Here we demonstrate a protective role for endogenous COX-derived products in a murine model of acetaminophen (APAP)-induced acute liver injury. A single hepatotoxic dose caused the selective induction of COX-2 mRNA and increased PGD2 and PGE2 levels within the livers of COX(+/+) male mice suggesting a role for COX-2 in this model of liver injury. APAP-induced hepatotoxicity and lethality were markedly greater in COX-2(-/-) and (-/+) mice in which normal PG responsiveness is altered. The significantly increased toxicity linked to COX-2 deficiency could be mimicked using the selective COX-2 inhibitory drug, celecoxib, in COX(+/+) mice and was not due to alterations in drug-protein adduct formation, a surrogate for bioactivation and toxicity. Microarray analyses indicated that increased injury associated with COX-2 deficiency coincided, most notably, with a profoundly impaired induction of heat shock proteins in COX-2(-/+) mice suggesting that PGs may act as critical endogenous stress signals following drug insult. These findings suggest that COX-2-derived mediators serve an important hepato-protective function and that COX inhibition may contribute to the risk of drug-induced liver injury, possibly through both nonimmunological and immunological pathways.

Topics: Acetaminophen; Animals; Celecoxib; Chemical and Drug Induced Liver Injury; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; DNA Primers; Gene Expression Profiling; Immunoblotting; Isoenzymes; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides; Survival Rate

To investigate the effective ingredients of Salvia miltiorrhizae on anti-liver injury, the water soluble component of the above drug, magnesium lithosperamate B, was used to conduct the experimental treatment of acute liver injury by D-galactosamine (10 mg/kg body weight, orally). The results showed that the component could obviously attenuate the necrosis of liver tissues, lower the activities of serum alanine amino transferase (ALT) and aspartate amino transferase (AST), P < 0.05. Compared with those of the normal rats, the levels of the products of cyclo-oxygenase (6-keto-prostaglandin F1 alpha, prostaglandin D2 and total prostaglandins) in the metabolism of arachidonic acid in non-parenchymal cells of acute liver-injured rats were markedly decreased (P < 0.05). These data revealed that magnesium lithosperamate B might be one of the main components of Salvia miltiorrhizae in anti-liver injury, while increasing the levels of total prostaglandins in liver non-parenchymal cells was perhaps one of the mechanisms of anti-liver injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Galactosamine; Liver; Male; Prostaglandin D2; Rats; Rats, Wistar