Acetaminophen toxicity induces mitochondrial complex I inhibition in human liver tissue

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 - 2020/1/1

Y1 - 2020/1/1

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

SN - 1742-7835

JO - Basic & Clinical Pharmacology & Toxicology

JF - Basic & Clinical Pharmacology & Toxicology

ER -