Endoplasmic reticulum-targeted inhibition of CYP2E1 with vitamin E nanoemulsions alleviates hepatocyte oxidative stress and reverses alcoholic liver disease

• Published in: Biomaterials 2022-09, Vol.288, p.121720-121720, Article 121720
• Main Authors: Shi, Yingying, Liu, Yu, Wang, Sijie, Huang, Jiaxin, Luo, Zhenyu, Jiang, Mengshi, Lu, Yichao, Lin, Qing, Liu, Huihui, Cheng, Ningtao, You, Jian
• Format: Article
• Language: English
• Subjects: Alcoholic liver disease; CYP2E1; Endoplasmic reticulum; ROS; Vitamin E nanoemulsions
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2022.121720

Alcoholic liver disease (ALD) is a global healthcare problem and socioeconomic issue that is primarily driven by chronic and/or excessive alcohol consumption. Upon alcohol exposure, parenchymal hepatocytes (HCs) up-regulate endoplasmic reticulum (ER)-localized monooxygenase Cytochrome P450 family 2 subfamily E member 1 (CYP2E1) to accelerate the metabolism of ethanol (EtOH), which concurrently exacerbates the production and accumulation of toxic metabolic intermediates, especially reactive oxygen species (ROS), playing a decisive role in the initiation and perpetuation of alcohol-induced liver injury. ALD patients without timely intervention may develop a spectrum of metabolic and functional disorders in the liver, including hepatic steatosis, hepatitis, fibrosis, and even cirrhosis. However, up to now, there have been no FDA-approved pharmacological or nutritional therapeutics for treating patients with ALD, and an effective amelioration of alcohol-induced hepatotoxicity with satisfactory biosafety is still demanding. In this study, antioxidant Vitamin E-incorporating nanoemulsions modified with ER-targetable small molecule p-dodecylbenzene sulfonamide (p-DBSN) was constructed to load and deliver CYP2E1 inhibitor Clomethiazole (CMZ) to the ER of HCs for site-specific inhibition, which displayed remarkable hepatoprotective effects against chronic alcohol exposure without off-target toxicity, both intravenously injected and orally administrated. Generally, our work may provide a promising nanoplatform for reversing ALD. Here, Vitamin E-incorporating nanoemulsions was constructed to load and deliver Cytochrome P450 family 2 subfamily E member 1 (CYP2E1) inhibitor Clomethiazole (CMZ) to the endoplasmic reticulum (ER) of hepatocytes, which mitigated hepatic oxidative stress upon ethanol exposure, reversing alcoholic liver disease (ALD). [Display omitted]