Trumper L, Monasterolo L A, Elías M M
Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Repúblíca Argentina.
J Pharmacol Exp Ther. 1996 Nov;279(2):548-54.
The role of hepatically derived metabolites was studied in rats treated with a nephrotoxic dose of acetaminophen (APAP, 1000 mg/kg b.wt. i.p.). Hepatic glutathione (GSH) content 16 h after APAP dosing was significantly decreased (control = 3.83 +/- 0.1, APAP = 2.51 +/- 0.3 mumol/g wet tissue), whereas renal GSH levels were not changed. The role of hepatically derived GSH conjugates was investigated by administering the gamma-glutamyl-transpeptidase inhibitor, acivicin (20 mg/kg b.wt. i.p.). Treatment with acivicin led to a significant decrease in hepatic and renal gamma-glutamyltranspeptidase activity. Administration of acivicin 1 h before APAP administration protected against the alterations of glomerular filtration rate and urea and creatinine plasma levels induced by APAP. The appearance of epithelial cells and granular casts as well as the urinary excretion of protein and glucose were decreased compared with rats not pretreated with acivicin. Hepatocellular damage (evaluated by glutamic pyruvic transaminase levels) induced by APAP was not altered by acivicin pretreatment. APAP plasma levels and its urinary excretion were the same whether the rats were pretreated with acivicin or not. A group of rats was fitted with an exteriorized biliary cannula before APAP administration to study the contribution of the biliary excretion route of APAP metabolites in the APAP-induced renal damage. No differences were observed on APAP-induced renal effects between rats cannulated or not. Our results suggest that hepatically derived APAP metabolites are partially responsible for APAP renal effects. The sinusoidal efflux of these metabolites is also suggested.
研究了肝源性代谢产物在给予肾毒性剂量对乙酰氨基酚（APAP，1000mg/kg体重，腹腔注射）的大鼠中的作用。APAP给药16小时后，肝脏谷胱甘肽（GSH）含量显著降低（对照组=3.83±0.1，APAP组=2.51±0.3μmol/g湿组织），而肾脏GSH水平未改变。通过给予γ-谷氨酰转肽酶抑制剂阿西维辛（20mg/kg体重，腹腔注射）来研究肝源性GSH缀合物的作用。用阿西维辛治疗导致肝脏和肾脏γ-谷氨酰转肽酶活性显著降低。在APAP给药前1小时给予阿西维辛可预防APAP诱导的肾小球滤过率、尿素和肌酐血浆水平的改变。与未用阿西维辛预处理的大鼠相比，上皮细胞和颗粒管型的出现以及蛋白质和葡萄糖的尿排泄减少。阿西维辛预处理未改变APAP诱导的肝细胞损伤（通过谷丙转氨酶水平评估）。无论大鼠是否用阿西维辛预处理，APAP血浆水平及其尿排泄均相同。一组大鼠在给予APAP前安装了外置胆管插管，以研究APAP代谢产物的胆汁排泄途径在APAP诱导的肾损伤中的作用。插管大鼠和未插管大鼠在APAP诱导的肾脏效应方面未观察到差异。我们的结果表明，肝源性APAP代谢产物部分介导了APAP的肾脏效应。还提示了这些代谢产物的窦状隙流出。
