Valentovic Monica, Terneus Marcus, Harmon R Christopher, Carpenter A Betts
Department of Pharmacology, Joan C. Edwards School of Medicine, Marshall University, 1532 Spring Valley Drive, Huntington, WV 25704-9388, USA.
Toxicol Lett. 2004 Dec 30;154(3):165-74. doi: 10.1016/j.toxlet.2004.07.010.
Hepatic toxicity is associated with excessive dosages of the over the counter analgesic, acetaminophen (APAP). The aim of this study was to explore protection by the nutritional agent S-adenosylmethionine (SAMe) on APAP hepatotoxicity. Male C57BL/6 mice were injected intraperitoneal (i.p.) with 500 mg/kg (15 ml/kg) APAP or water vehicle (VEH). SAMe was injected i.p. at a dose of either 1000 mg/kg (5 ml/kg) just prior or 500 mg/kg SAMe 15 min prior to administration of VEH or APAP. Comparison of groups showed that SAMe reduced APAP toxicity. Plasma alanine aminotransferase (ALT) levels were increased 2 and 4 h after APAP administration when compared to vehicle (VEH) controls. Liver weight was increased relative to the VEH group within 4 h after APAP treatment. Histological examination by light microscopy confirmed small changes in morphology within 2 h after APAP injection and marked centrilobular necrosis within 4 h in the APAP group. In contrast, when APAP was administered to SAMe pretreated mice, ALT and liver weights were comparable to the VEH and SAMe groups. Histological examination also showed that SAMe produced a marked protection in APAP mediated centrilobular necrosis at 4 h after APAP injection. APAP administration depressed hepatic glutathione levels when monitored at 2 and 4 h. Lipid peroxidation was induced above VEH values 2 and 4 h after APAP injection. Consistent with the SAMe protection of APAP hepatic toxicity, the expected depletion of hepatic glutathione (GSH) levels by APAP was prevented by SAMe pretreatment. SAMe pretreatment also prevented the induction of lipid peroxidation at 2 and 4 h post-APAP administration. In conclusion, SAMe provides protection from APAP hepatic toxicity at 2 and 4 h post-APAP injection. SAMe pretreatment prevented APAP associated depletion in hepatic glutathione and induction of lipid peroxidation as part of its mechanism of protection.
肝毒性与非处方镇痛药对乙酰氨基酚（APAP）的过量服用有关。本研究的目的是探讨营养剂S-腺苷甲硫氨酸（SAMe）对APAP肝毒性的保护作用。雄性C57BL/6小鼠腹腔注射500mg/kg（15ml/kg）APAP或溶媒（VEH）。SAMe以1000mg/kg（5ml/kg）的剂量在给药前即刻腹腔注射，或以500mg/kg的剂量在给予VEH或APAP前15分钟腹腔注射。组间比较显示SAMe可降低APAP毒性。与溶媒（VEH）对照组相比，APAP给药后2小时和4小时血浆丙氨酸转氨酶（ALT）水平升高。APAP治疗后4小时内，肝脏重量相对于VEH组增加。光学显微镜组织学检查证实，APAP注射后2小时内形态学有微小变化，APAP组4小时内有明显的小叶中心坏死。相比之下，当给SAMe预处理的小鼠注射APAP时，ALT和肝脏重量与VEH组和SAMe组相当。组织学检查还显示，SAMe对APAP注射后4小时的APAP介导的小叶中心坏死有显著保护作用。在2小时和4小时监测时，APAP给药会降低肝脏谷胱甘肽水平。APAP注射后2小时和4小时，脂质过氧化水平高于VEH组。与SAMe对APAP肝毒性的保护作用一致，SAMe预处理可防止APAP导致的肝脏谷胱甘肽（GSH）水平预期性降低。SAMe预处理还可防止APAP给药后2小时和4小时脂质过氧化的诱导。总之，SAMe在APAP注射后2小时和4小时可提供对APAP肝毒性的保护。SAMe预处理可防止APAP导致的肝脏谷胱甘肽耗竭和脂质过氧化诱导，这是其保护机制的一部分。
