Assessing Platelet Mitochondrial Dysfunction in a Murine Model of Acute Acetaminophen Toxicity.

Autor: Fox C; Department of Emergency Medicine, Atrium Health's Carolinas Medical Center, 1000 Blythe Blvd., Medical Education Building 3rd Floor, Charlotte, NC, 28203, USA., Ekaney ML; Department of Surgery, Atrium Health's Carolinas Medical Center, 1000 Blythe Blvd., Cannon Research Building, Charlotte, NC, 28203, USA., Runyon M; Department of Emergency Medicine, Atrium Health's Carolinas Medical Center, 1000 Blythe Blvd., Medical Education Building 3rd Floor, Charlotte, NC, 28203, USA., Nguyen HM; Center for Outcomes Research and Evaluation (CORE), 1300 Scott Ave, Office 124, Charlotte, NC, 28204, USA., Turk PJ; Department of Data Science, University of Mississippi Medical Center, 2500 N State St, Jackson, MS, 39216, USA., McKillop IH; Department of Surgery, Atrium Health's Carolinas Medical Center, 1000 Blythe Blvd., Cannon Research Building, Charlotte, NC, 28203, USA., Murphy CM; Department of Emergency Medicine, Atrium Health's Carolinas Medical Center, 1000 Blythe Blvd., Medical Education Building 3rd Floor, Charlotte, NC, 28203, USA. christine.murphy@atriumhealth.org.
Jazyk: angličtina
Zdroj: Journal of medical toxicology : official journal of the American College of Medical Toxicology [J Med Toxicol] 2023 Oct; Vol. 19 (4), pp. 341-351. Date of Electronic Publication: 2023 Aug 29.
DOI: 10.1007/s13181-023-00964-0
Abstrakt: Introduction: Acetaminophen (APAP) toxicity remains a significant cause of adult and pediatric liver failure in North America and Europe. Previous research has evaluated the impaired mitochondrial function associated with APAP toxicity. The primary aim of this study was to evaluate the effects of APAP toxicity on platelet mitochondrial function using platelet oxygen consumption in a murine model in vivo. Our secondary objectives were to determine the effect of 4-MP on platelet mitochondrial function and hepatic toxicity in the setting of APAP overdose, and to correlate platelet mitochondrial function with other markers of APAP toxicity.
Methods: Male C57Bl/6 mice were randomized to receive APAP (300 or 500 mg/kg) or vehicle followed 90 minutes later by either 4-MP (50 mg/kg) or vehicle via intraperitoneal injection. Mice were euthanized 0, 12, or 24 hours later and platelets isolated from cardiac blood and counted. Platelet oxygen consumption (POC) was determined using a closed-system respirometer. Liver injury was assessed by measuring alanine transferase (ALT) and histological evaluation.
Results: Injection of 500 mg/kg APAP led to increased POC versus pair-matched control (vehicle) (p < 0.001). Administration of 4-MP did not affect POC in control or 300 mg/kg APAP mice. In mice receiving 500 mg/kg APAP and 4-MP, POC decreased significantly compared to mice receiving 500 mg/kg APAP alone (p < 0.01). Serum and histological analysis confirmed APAP-induced hepatic damage in mice receiving 500 mg/kg APAP and these effects blunted by treatment with 4-MP.
Conclusions: Platelet oxygen consumption as a measure of mitochondrial function may be useful as a biomarker of hepatic APAP toxicity in the setting of moderate to severe overdose. Treatment with 4-MP decreases hepatic necrosis and may mitigate the harmful effects of APAP on platelet mitochondrial function detected via POC.
(© 2023. American College of Medical Toxicology.)
Databáze: MEDLINE
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