Correlation of MCP1 with toxicity in acetaminophen overdose

Abstract

Purpose Studies in animal models of acetaminophen (APAP) toxicity have reported the upregulation of cytokines, some of which are anti‐inflammatory or involved in hepatocyte regeneration. To further study this relationship, cytokines were measured in children/adolescents with acute APAP overdose. Methods: ELISA measurements of IL6, IL8, IL10, and MCP1 were performed on serum samples of APAP overdose patients. Results: 76 patients (age 13.72±4.41 yrs; 64 females) were enrolled and stratified by toxicity subgroups: Grp 1 (no/mild toxicity; AST<100 IU/L, n=51), Grp 2 (moderate toxicity; AST≥100 & ≥1000 IU/L, n=12), Grp 3 (severe toxicity, AST>1000 IU/L, n=13). A significant relationship was present for MCP1 (presented as median, range) (Grp 1, 628.0 pg/mL, 181.6‐1800.4; Grp 2, 1137.3 pg/mL, 167.8‐1808.1; Grp 3, 2777.1 pg/mL, 472.6‐6291.3) and toxicity subgroups (p<0.001). PT was higher (17.6 sec, 11.4‐43.8 vs. 14.1 sec, 10.6‐27.5; p<0.001) in patients with elevated MCP1 and in patients with delays in N‐acetylcysteine (p<0.0003). Grp 2+3 had higher values for IL6 (5.3 pg/mL, 0.0‐58.3, p=0.023) than Grp 1 (0.0 pg/mL, 0.0‐35.2) and higher values for IL8 (17.6 pg/mL, 0.0‐1013.8, p=0.027) than Grp 1 (0.0pg/mL, 0.0–1278.3). Conclusions: MCP1, a cytokine with hepatoprotective properties, appears to have a strong relationship with clinical measures of toxicity/risk in APAP overdose. This study supports the involvement of cytokines in repair processes in APAP toxicity. Clinical Pharmacology & Therapeutics (2004) 75, P50–P50; doi:

Acetaminophen Overdose Enhances Early Cholangiocarcinoma in Opisthorchiasis Hamsters

“…However severe liver injury, liver failure and even death can occur with misuse and overdose. (Davidson and Eastham, 1966;Gow et al, 1997;Bernal et al, 1998a;Bernal et al, 1998b;Makin et al, 1998;Gow et al, 1999;Larson et al, 2006;Sood et al, 2013) and animal models (Banda and Quart, 1987;Dalhoff et al, 1991;Knight et al, 2003;James et al, 2004;LoGuidice and Boelsterli, 2011;Yang et al, 2012;Bhushan et al, 2013). Acetaminophen metabolism by cytochrome P450 2E1 to hepatotoxic N-acetyl-pbenzoquinoneimine (NAPQI) which depletes glutathione (GSH) induces oxidative stress lipid peroxidation (LPO) mitochondrial dysfunction and DNA fragmentation which results in hepatocyte necrosis, liver damage and death (Nelson, 1990;Rashed et al, 1990;Tirmenstein and Nelson, 1990;Cohen and Khairallah, 1997;James et al, 2001a;James et al, 2001b;James et al, 2003a;James et al, 2003b).…”

The Role of Mechanistic Biomarkers in Understanding Acetaminophen Hepatotoxicity in Humans

“…The most consistently elevated cytokines in APAP overdose patients appear to be interleukin (IL)-6, IL-8, and monocyte chemoattractant protein 1 (MCP1) (James et al, 2001(James et al, , 2004(James et al, , 2005Williams et al, 2003;Woolbright et al, 2022). Of these, the role of IL-6 in APAP toxicity has been most thoroughly investigated in experimental models.…”