Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu 600 077, India.
Environ Toxicol Pharmacol. 2023 Apr;99:104093. doi: 10.1016/j.etap.2023.104093. Epub 2023 Mar 2.
Thioacetamide (TAA) undergoes bioactivation in the liver by the CYP450 2E1 enzyme, resulting in the formation of TAA-S-oxide and TAA-S-dioxide. TAA-S-dioxide induces oxidative stress via lipid peroxidation of the hepatocellular membrane. A single TAA dose (50-300 mg/kg) administration initiates hepatocellular necrosis around the pericentral region after its covalent binding to macromolecules in the liver. Intermittent TAA administration (150-300 mg/kg, weekly thrice, for 11-16 weeks) activates transforming growth factor (TGF)-β/smad3 downstream signaling in injured hepatocytes, causing hepatic stellate cells (HSCs) to acquire myofibroblast like phenotype. The activated HSCs synthesize a variety of extracellular matrix, leading to liver fibrosis, cirrhosis, and portal hypertension. The TAA induced liver injury varies depending on the animal model, dosage, frequency, and routes of administration. However, TAA induces hepatotoxicity in a reproducible manner, and it is an ideal model to evaluate the antioxidant, cytoprotective, and antifibrotic compounds in experimental animals.
硫代乙酰胺（TAA）在肝脏中被 CYP450 2E1 酶生物激活，形成 TAA-S-氧化物和 TAA-S-二氧化物。TAA-S-二氧化物通过肝细胞膜的脂质过氧化诱导氧化应激。单次 TAA 剂量（50-300mg/kg）给药后，在与肝内大分子共价结合后，引发中央区周围的肝细胞坏死。间歇性 TAA 给药（150-300mg/kg，每周三次，共 11-16 周）激活受损肝细胞中转化生长因子（TGF）-β/smad3 下游信号通路，导致肝星状细胞（HSCs）获得肌成纤维细胞样表型。活化的 HSCs 合成多种细胞外基质，导致肝纤维化、肝硬化和门静脉高压。TAA 诱导的肝损伤取决于动物模型、剂量、频率和给药途径。然而，TAA 以可重复的方式诱导肝毒性，是评估实验动物中抗氧化剂、细胞保护剂和抗纤维化化合物的理想模型。
