Potential role of activated macrophages in acetaminophen hepatotoxicity

Expression Profiling of Acetaminophen Liver Toxicity in Mice Using Microarray Technology

“…The role(s) that LRG-21 plays during drug-induced liver toxicity is unknown. However, one could hypothesize that LRG-21 may play dual roles in the liver: It may be involved in (a) the activation of resident macrophages (Kupffer cells) necessary for the development of APAP-induced liver damage (14,15) and (b) the modulation of signaling pathways that, in turn, prevent an immune mediated response against drug-protein adducts by inducing apoptosis of drug-specific T cells. These possibilities certainly warrant further study.…”

“…1). Recent studies have linked SOCS expression with the down-modulation of macrophage activity (41), suggesting that SOCS induction may be part of an adaptive response limiting the role of resident macrophages (14,15) in APAP-induced liver toxicity. The fact that SOCS induction may be mediated by IFN-␤ signaling (41), whose expression also increased following APAP treatment (Table 2), supports this hypothesis.…”

“…It continues to be a significant cause of liver injury and lethality in humans (2). Studies have suggested that APAP-induced liver injury may be related to protein arylation (3), oxidative stress (4 -6), disruption of calcium (7,8) and mitochondrial homeostasis (9), alteration of transcription pathways (10 -12), proinflammatory signaling (13)(14)(15), and the induction of cell death pathways (2). However, the precise molecular events occurring within the liver following APAP insult have still not been deciphered, and only a limited number of pathways involved in controlling toxicity progression have been identified (6,16).…”

Two-dimensional database of mouse liver proteins: Changes in hepatic protein levels following treatment with acetaminophen or its nontoxic regioisomer 3-acetamidophenol

“…Nevertheless, arguments have been put forward to support that oxidative stress, increases in cytoplasmic calcium, and mitochondrial disruption observed after exposure to toxic doses of APAP are involved in the progression of toxicity rather than in its initiation [1,15]. Furthermore, the involvement of nonparenchymal Kupffer cells in the acetaminophen-induced toxicity has also been described [16], but this process is likely to be a response to already damaged hepatocytes rather than the cause of hepatic damage.…”

Cytotoxicity and cytoprotective activities of natural compounds. The case of curcumin

“…It was speculated that hepatocytes damaged by paracetamol release factors which activate Kupfer cells. T h e activated Kupfer cells subsequently release cytotoxic cytokines and reactive oxygen species, which further damage the hepatocytes leading to cell death (Laskin 1986, Laskin et al 1995.…”