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Acetaminophen toxicity induces mitochondrial complex I inhibition in human liver tissue

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@article{ca1f83b6d5b940f78027cb71886c78de,
title = "Acetaminophen toxicity induces mitochondrial complex I inhibition in human liver tissue",
abstract = "Acetaminophen (APAP) is used worldwide and is regarded as safe in therapeutic concentrations but can cause acute liver failure in higher doses. High doses of APAP have been shown to inhibit complex I and II mitochondrial respiratory capacity in mouse hepatocytes, but human studies are lacking. Here, we studied mitochondrial respiratory capacity in human hepatic tissue ex vivo with increasing doses of APAP. Hepatic biopsies were obtained from 12 obese patients who underwent a Roux-en-Y gastric bypass (RYGB) or a sleeve gastrectomy surgery. Mitochondrial respiration was measured by high-resolution respirometry. Therapeutic concentrations (≤0.13 mmol/L) of APAP did not inhibit state 3 complex I-linked respiration. APAP concentrations of ≥2.0 mmol/L in the medium significantly reduced hepatic mitochondrial respiration in a dose-dependent manner. Complex II-linked mitochondrial respiration was not inhibited by APAP. We conclude that the mitochondrial respiratory capacity is affected by a hepato-toxic effect of APAP, which involved complex I, but not complex II.",
keywords = "Acetaminophen (APAP), drug-induced liver injury, hepatotoxicity, mitochondrial respiratory capacity, overdose",
author = "{Maise Chr{\o}is}, Karoline and Steen Larsen and {Steen Pedersen}, Julie and {Opseth Rygg}, Marte and {Elisabeth Bruun Boilesen}, Astrid and Flemming Bendtsen and Flemming Dela",
note = "{\circledC} 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).",
year = "2019",
month = "8",
day = "12",
doi = "10.1111/bcpt.13304",
language = "English",
journal = "Basic & Clinical Pharmacology & Toxicology Online",
issn = "1742-7843",
publisher = "Wiley-Blackwell Publishing Ltd",

}

RIS

TY - JOUR

T1 - Acetaminophen toxicity induces mitochondrial complex I inhibition in human liver tissue

AU - Maise Chrøis, Karoline

AU - Larsen, Steen

AU - Steen Pedersen, Julie

AU - Opseth Rygg, Marte

AU - Elisabeth Bruun Boilesen, Astrid

AU - Bendtsen, Flemming

AU - Dela, Flemming

N1 - © 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

PY - 2019/8/12

Y1 - 2019/8/12

N2 - Acetaminophen (APAP) is used worldwide and is regarded as safe in therapeutic concentrations but can cause acute liver failure in higher doses. High doses of APAP have been shown to inhibit complex I and II mitochondrial respiratory capacity in mouse hepatocytes, but human studies are lacking. Here, we studied mitochondrial respiratory capacity in human hepatic tissue ex vivo with increasing doses of APAP. Hepatic biopsies were obtained from 12 obese patients who underwent a Roux-en-Y gastric bypass (RYGB) or a sleeve gastrectomy surgery. Mitochondrial respiration was measured by high-resolution respirometry. Therapeutic concentrations (≤0.13 mmol/L) of APAP did not inhibit state 3 complex I-linked respiration. APAP concentrations of ≥2.0 mmol/L in the medium significantly reduced hepatic mitochondrial respiration in a dose-dependent manner. Complex II-linked mitochondrial respiration was not inhibited by APAP. We conclude that the mitochondrial respiratory capacity is affected by a hepato-toxic effect of APAP, which involved complex I, but not complex II.

AB - Acetaminophen (APAP) is used worldwide and is regarded as safe in therapeutic concentrations but can cause acute liver failure in higher doses. High doses of APAP have been shown to inhibit complex I and II mitochondrial respiratory capacity in mouse hepatocytes, but human studies are lacking. Here, we studied mitochondrial respiratory capacity in human hepatic tissue ex vivo with increasing doses of APAP. Hepatic biopsies were obtained from 12 obese patients who underwent a Roux-en-Y gastric bypass (RYGB) or a sleeve gastrectomy surgery. Mitochondrial respiration was measured by high-resolution respirometry. Therapeutic concentrations (≤0.13 mmol/L) of APAP did not inhibit state 3 complex I-linked respiration. APAP concentrations of ≥2.0 mmol/L in the medium significantly reduced hepatic mitochondrial respiration in a dose-dependent manner. Complex II-linked mitochondrial respiration was not inhibited by APAP. We conclude that the mitochondrial respiratory capacity is affected by a hepato-toxic effect of APAP, which involved complex I, but not complex II.

KW - Acetaminophen (APAP)

KW - drug-induced liver injury

KW - hepatotoxicity

KW - mitochondrial respiratory capacity

KW - overdose

UR - http://www.scopus.com/inward/record.url?scp=85071765516&partnerID=8YFLogxK

U2 - 10.1111/bcpt.13304

DO - 10.1111/bcpt.13304

M3 - Journal article

JO - Basic & Clinical Pharmacology & Toxicology Online

JF - Basic & Clinical Pharmacology & Toxicology Online

SN - 1742-7843

ER -

ID: 57797514