Bacterial- and Viral-Induced Inflammation Increases Sensitivity to Acetaminophen Hepatotoxicity

Abstract

Acetaminophen (APAP)-induced hepatotoxicity accounts for nearly half of acute liver failure cases in the United States. The doses that produce hepatotoxicity vary considerably and many risk factors have been proposed, including liver inflammation from viral hepatitis. Interestingly, inflammatory stress from another stimulus, bacterial endotoxin (lipopolysaccharide, LPS), renders the liver more sensitive to hepatotoxicity from numerous xenobiotic agents. The purpose of these studies was to test the hypothesis that inflammation induced by LPS or infection with reovirus increases sensitivity to APAP-induced liver injury. For LPS-induced inflammation, C57BL/6J mice were treated with either saline or LPS (44 x 10(6) EU/kg, ip) 2 h before treatment with APAP (100-400 mg/kg, ip) or saline. No elevation in serum alanine aminotransferase (ALT) activity was observed in mice that received vehicle or LPS alone. LPS co-treatment produced a leftward shift of the dose-response curve for APAP-induced hepatotoxicity and led to significantly greater tumor necrosis factor-alpha (TNF) production than APAP alone. Reovirus serotype 1 (10(8) PFU, iv) induced inflammation in Balb/c mice as evidenced by increases in hepatic mRNAs for macrophage inhibitory protein-2, interleukin-6, and TNF. Co-administration of reovirus and APAP at doses of 450 and 700 mg/kg (2 h after reovirus) led to increases in serum ALT activity, whereas neither reovirus nor APAP alone produced liver injury. Consistent with the increases in serum ALT activity, histopathologic examination revealed centrilobular necrosis with marked neutrophilic accumulation only in livers of mice treated with LPS/APAP or with reovirus/APAP. The results suggest that normally noninjurious doses of APAP are rendered hepatotoxic by modest inflammation, whether bacterial or viral in origin.

Intrinsic versus Idiosyncratic Drug-Induced Hepatotoxicity—Two Villains or One?

“…Indeed, APAP consumption interacts in humans with hepatitis viruses (i.e., inflammagens that target the liver) to increase the risk for serious liver injury (Yaghi et al, 2006: Moling et al, 2006Kc, 2007;Nguyen et al, 2008). Likewise, we reported recently that infection of mice with a virus that induced hepatic inflammation rendered nontoxic doses of APAP hepatotoxic (Maddox et al, 2010).…”

“…jpet.aspetjournals.org systemic exposure to LPS, presumably by increasing intestinal permeability to this inflammagen Bode, 2003, 2005;Purohit et al, 2008). It is noteworthy that mice treated with a modestly inflammatory dose of LPS became more sensitive to APAP-induced liver injury; that is, LPS coexposure caused a leftward shift in the dose-response curve for APAP hepatotoxicity, causing normally nontoxic doses of APAP to become hepatotoxic (Maddox et al, 2010). Thus, the ability of ethanol to enhance intestinal translocation of LPS to the liver is likely to play a role in its hepatotoxic interaction with APAP.…”

Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

“…20 The hepatotoxicity of many xenobiotics has been augmented in LPS-treated animals. [22][23][24] On the other side, malaria infection is associated with an inflammatory response in many tissues including liver. [25][26][27] Immune cells are aggregated in the liver of malaria-infected patients.…”

Regular paracetamol in severe dengue: a lethal combination?

“…(12) There have been evidences, however, both in vitro and in vivo, that the metabolism of PCM is reduced in patients with hepatitis. (13,14) Although at present, there is no study on the metabolism of PCM in cases of dengue complicated by concomitant hepatitis, it is likely that the result may be significant. The new WHO guidelines on DF allows PCM to be prescribed to relieve discomfort from fever.…”