Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Department of Chemistry, Centre for Analysis and Synthesis, Lund University, Lund, Sweden.
Basic Clin Pharmacol Toxicol. 2018 Nov;123(5):589-593. doi: 10.1111/bcpt.13058. Epub 2018 Jul 9.
Paracetamol overdosing may cause liver injury including fulminant liver failure due to generation of the toxic metabolites, N-acetyl-p-benzoquinone imine (NAPQI) and p-benzoquinone (p-BQ). Herein, the chelating agent, N,N'-Bis(2-mercaptoethyl)isophthalamide (NBMI), was examined for its potential ability to entrap NAPQI and p-BQ and to prevent paracetamol-induced liver injury. Both NBMI and the conventional paracetamol antidote N-acetylcysteine (NAC) were investigated with regard to their abilities to scavenge the NAPQI and p-BQ in a Transient Receptor Potential Ankyrin 1-dependent screening assay. Stoichiometric evaluations indicated that NBMI was able to entrap these metabolites more efficiently than NAC. Furthermore, oral administration of either NBMI (680 mg/kg) or NAC (680 mg/kg) prevented the development of the characteristic liver necrosis and elevation of serum alanine aminotransferase in a mouse model for paracetamol-induced liver injury. In summary, these results show that NBMI is able to entrap the toxic metabolites NAPQI and p-BQ and to prevent paracetamol-induced liver injury in mice.
对乙酰氨基酚过量可能会导致肝损伤，包括暴发性肝衰竭，这是由于有毒代谢物 N-乙酰苯醌亚胺 (NAPQI) 和对苯醌 (p-BQ) 的生成。在此，研究了螯合剂 N,N'-双(2-巯基乙基)异酞酰胺 (NBMI) 捕获 NAPQI 和 p-BQ 并预防对乙酰氨基酚引起的肝损伤的潜在能力。分别研究了 NBMI 和传统的对乙酰氨基酚解毒剂 N-乙酰半胱氨酸 (NAC) 清除瞬时受体电位锚蛋白 1 依赖性筛选试验中 NAPQI 和 p-BQ 的能力。化学计量评估表明，NBMI 能够比 NAC 更有效地捕获这些代谢物。此外，NBMI(680mg/kg)或 NAC(680mg/kg)的口服给药可预防在对乙酰氨基酚诱导的肝损伤的小鼠模型中特征性肝坏死的发展和血清丙氨酸氨基转移酶的升高。总之，这些结果表明，NBMI 能够捕获有毒代谢物 NAPQI 和 p-BQ，并预防小鼠的对乙酰氨基酚诱导的肝损伤。
