Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-? gene knockout mice

Abstract

Recent evidence suggests that macrophages and/or other nonparenchymal cells may release important mediators contributing to the hepatic necrosis induced by high doses of acetaminophen (APAP). The nature and causative role of these mediators has remained elusive, however. To investigate the role of the proinflammatory cytokine, tumor necrosis factor (TNF) in the initiation and early propagation of APAP-induced liver injury, we have used mice deficient in both TNF and the closely related lymphotoxin-␣ (LT-␣). Male TNF/LT-␣ knockout mice and C57BL/6 wild-type mice were treated with a hepatotoxic dose of APAP (400 mg/kg, intraperitoneally), and the development of liver injury was monitored over 8 hours. Both genotypes exhibited similar basal activities of hepatic cytochrome P450 2E1 and 1A2. After APAP administration, both the rate of glutathione consumption and the extent of subsequent selective protein binding did not differ significantly in the knockout and wild-type mice. The TNF/LT-␣-deficient mice developed severe centrilobular necrosis and exhibited highly increased levels of serum alanine aminotransferase and aspartate aminotransferase, the extent of which was not significantly different from that in wild-type mice. In C57BL/6 mice exposed to APAP, no increases in hepatic transcripts of TNF or LT-␣ were found by reverse transcription-polymerase chain reaction, nor was immunoreactive serum TNF detected by enzyme-linked immunosorbent assay over 8 hours posttreatment. These data indicate that, in the absence of the genes encoding for TNF and LT-␣, APAP bioactivation was not altered and mice still developed severe hepatic necrosis. Thus, TNF is unlikely to be a key mediator in the early pathogenesis of APAP-induced hepatotoxicity. (HEPATOLOGY 1998;27:1021-1029.)

Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-α-induced apoptosis in cultured mouse hepatocytes

“…38 Although nuclear apoptosis-like changes have been observed in vivo in the liver of APAP-treated mice, [6][7][8]19 the above-cited inhibition of caspase activity 36 and the lack of difference in extent of liver injury in TNF-␣ knockout mice suggest that apoptosis may not be an important factor. 39 However, both of these studies employed a single, large dose of APAP. Thus, it is conceivable that lower doses and careful quantitation of susceptibility to endogenous and exogenous TNF-␣ might reveal a population of hepatocytes behaving similarly to that which we observed with intermediate concentrations of APAP in culture.…”

Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment Ameliorate Acetaminophen-Induced Liver Injury in Mice via Central Cholinergic System Regulation

“…Decline in hepatic GSH level is a widely accepted marker for the generation of toxic reactive intermediates in vitro or in vivo (Boess et al, 1998). Previous studies have reported that GSH concentration was significantly reduced 1 hour after toxic exposure, remained low until 3 hours after exposure, and then started to recover (McGill et al, 2012;Williams et al, 2014).…”

Role of c-Jun N-terminal kinase (JNK) in regulating tumor necrosis factor-alpha (TNF-.ALPHA.) mediated increase of acetaminophen (APAP) and chlorpromazine (CPZ) toxicity in murine hepatocytes

“…In addition, Blazka et al against APAP-induced liver injury in mice. On the othon APAP toxicity in tumor necrosis factor/lymphotoxinalpha gene knockout mice (Boess et al, 1998). Recently, APAP was rendered hepatotoxic in mice by an otherwise nontoxic dose of LPS (Newport et al, 2005).…”