Acetaminophen toxicity induces mitochondrial complex I inhibition in human liver tissue
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Acetaminophen toxicity induces mitochondrial complex I inhibition in human liver tissue. / Chrøis, Karoline Maise; Larsen, Steen; Pedersen, Julie Steen; Rygg, Marte Opseth; Boilsen, Astrid Elisabeth Bruun; Bendtsen, Flemming; Dela, Flemming.
In: Basic & Clinical Pharmacology & Toxicology, Vol. 126, No. 1, 2020, p. 86-91.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Acetaminophen toxicity induces mitochondrial complex I inhibition in human liver tissue
AU - Chrøis, Karoline Maise
AU - Larsen, Steen
AU - Pedersen, Julie Steen
AU - Rygg, Marte Opseth
AU - Boilsen, Astrid Elisabeth Bruun
AU - Bendtsen, Flemming
AU - Dela, Flemming
N1 - © 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).
PY - 2020
Y1 - 2020
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.
U2 - 10.1111/bcpt.13304
DO - 10.1111/bcpt.13304
M3 - Journal article
C2 - 31403256
VL - 126
SP - 86
EP - 91
JO - Basic and Clinical Pharmacology and Toxicology
JF - Basic and Clinical Pharmacology and Toxicology
SN - 1742-7835
IS - 1
ER -
ID: 228208024