Chang Geng-Ruei, Hou Po-Hsun, Yang Wei-Cheng, Wang Chao-Min, Fan Pei-Shan, Liao Huei-Jyuan, Chen To-Pang
Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan.
Department of Psychiatry, Taichung Veterans General Hospital, 1650 Taiwan Boulevard (Section 4), Taichung 40705, Taiwan.
Pharmaceuticals (Basel). 2021 Mar 16;14(3):267. doi: 10.3390/ph14030267.
Doxepin is commonly prescribed for depression and anxiety treatment. Doxepin-related disruptions to metabolism and renal/hepatic adverse effects remain unclear; thus, the underlying mechanism of action warrants further research. Here, we investigated how doxepin affects lipid change, glucose homeostasis, chromium (Cr) distribution, renal impairment, liver damage, and fatty liver scores in C57BL6/J mice subjected to a high-fat diet and 5 mg/kg/day doxepin treatment for eight weeks. We noted that the treated mice had higher body, kidney, liver, retroperitoneal, and epididymal white adipose tissue weights; serum and liver triglyceride, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine levels; daily food efficiency; and liver lipid regulation marker expression. They also demonstrated exacerbated insulin resistance and glucose intolerance with lower Akt phosphorylation, GLUT4 expression, and renal damage as well as higher reactive oxygen species and interleukin 1 and lower catalase, superoxide dismutase, and glutathione peroxidase levels. The treated mice had a net-negative Cr balance due to increased urinary excretion, leading to Cr mobilization, delaying hyperglycemia recovery. Furthermore, they had considerably increased fatty liver scores, paralleling increases in adiponectin, FASN, PNPLA3, mRNA, and mRNA levels. In conclusion, doxepin administration potentially worsens renal injury, nonalcoholic fatty liver disease, and diabetes.
多塞平常用于治疗抑郁症和焦虑症。多塞平对代谢的干扰以及肾脏/肝脏的不良反应尚不清楚；因此，其潜在作用机制值得进一步研究。在此，我们研究了多塞平如何影响高脂饮食并接受5毫克/千克/天多塞平治疗八周的C57BL6/J小鼠的脂质变化、葡萄糖稳态、铬（Cr）分布、肾功能损害、肝损伤和脂肪肝评分。我们注意到，接受治疗的小鼠的体重、肾脏、肝脏、腹膜后和附睾白色脂肪组织重量更高；血清和肝脏甘油三酯、丙氨酸转氨酶、天冬氨酸转氨酶、血尿素氮和肌酐水平更高；每日食物效率更高；肝脏脂质调节标志物表达更高。它们还表现出胰岛素抵抗和葡萄糖耐量异常加剧，Akt磷酸化、GLUT4表达和肾损伤降低，以及活性氧、白细胞介素1水平升高，过氧化氢酶、超氧化物歧化酶和谷胱甘肽过氧化物酶水平降低。由于尿排泄增加，接受治疗的小鼠的铬净平衡为负，导致铬动员，延迟高血糖恢复。此外，它们的脂肪肝评分显著增加，与脂联素、脂肪酸合酶、帕他汀样磷脂酶域含蛋白3、mRNA和mRNA水平的增加平行。总之，服用多塞平可能会加重肾损伤、非酒精性脂肪性肝病和糖尿病。
