Chrøis Karoline Maise, Larsen Steen, Pedersen Julie Steen, Rygg Marte Opseth, Boilsen Astrid Elisabeth Bruun, Bendtsen Flemming, Dela Flemming
Xlab, Centre for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland.
Basic Clin Pharmacol Toxicol. 2020 Jan;126(1):86-91. doi: 10.1111/bcpt.13304. Epub 2019 Sep 4.
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.
对乙酰氨基酚（APAP）在全球范围内广泛使用，在治疗浓度下被认为是安全的，但高剂量时可导致急性肝衰竭。高剂量的APAP已被证明可抑制小鼠肝细胞中复合物I和II的线粒体呼吸能力，但缺乏人体研究。在此，我们研究了不同剂量APAP对离体人肝组织线粒体呼吸能力的影响。从12例接受Roux-en-Y胃旁路术（RYGB）或袖状胃切除术的肥胖患者获取肝活检组织。通过高分辨率呼吸测定法测量线粒体呼吸。治疗浓度（≤0.13 mmol/L）的APAP不抑制状态3复合物I相关的呼吸。培养基中≥2.0 mmol/L的APAP浓度以剂量依赖方式显著降低肝线粒体呼吸。复合物II相关的线粒体呼吸未被APAP抑制。我们得出结论，APAP的肝毒性作用会影响线粒体呼吸能力，该作用涉及复合物I，但不涉及复合物II。
