Ruiter-Lopez Leon, Khan Mohammed A S, Wang Xin, Song Byoung-Joon
Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Antioxidants (Basel). 2025 Feb 28;14(3):302. doi: 10.3390/antiox14030302.
Excessive alcohol consumption significantly impacts human health, particularly the brain, due to its susceptibility to oxidative stress, which contributes to neurodegenerative conditions. Alcohol metabolism in the brain occurs primarily via catalase, followed by CYP2E1 pathways. Excess alcohol metabolized by CYP2E1 generates reactive oxygen/nitrogen species (ROS/RNS), leading to cell injury via altering many different pathways. Elevated oxidative stress impairs autophagic processes, increasing post-translational modifications and further exacerbating mitochondrial dysfunction and ER stress, leading to cell death. The literature highlights that alcohol-induced oxidative stress disrupts autophagy and mitophagy, contributing to neuronal damage. Key mechanisms include mitochondrial dysfunction, ER stress, epigenetics, and the accumulation of oxidatively modified proteins, which lead to neuroinflammation and impaired cellular quality control. These processes are exacerbated by chronic alcohol exposure, resulting in the suppression of protective pathways like NRF2-mediated antioxidant responses and increased susceptibility to neurodegenerative changes in the brain. Alcohol-mediated neurotoxicity involves complex interactions between alcohol metabolism, oxidative stress, and autophagy regulation, which are influenced by various factors such as drinking patterns, nutritional status, and genetic/environmental factors, highlighting the need for further molecular studies to unravel these mechanisms and develop targeted interventions.
过量饮酒会对人体健康产生重大影响，尤其是对大脑，因为大脑易受氧化应激影响，而氧化应激会导致神经退行性疾病。大脑中的酒精代谢主要通过过氧化氢酶进行，其次是CYP2E1途径。CYP2E1代谢过量酒精会产生活性氧/氮物种（ROS/RNS），通过改变许多不同途径导致细胞损伤。氧化应激升高会损害自噬过程，增加翻译后修饰，并进一步加剧线粒体功能障碍和内质网应激，导致细胞死亡。文献强调，酒精诱导的氧化应激会破坏自噬和线粒体自噬，导致神经元损伤。关键机制包括线粒体功能障碍、内质网应激、表观遗传学以及氧化修饰蛋白的积累，这些都会导致神经炎症和细胞质量控制受损。长期接触酒精会加剧这些过程，导致NRF2介导的抗氧化反应等保护途径受到抑制，并增加大脑对神经退行性变化的易感性。酒精介导的神经毒性涉及酒精代谢、氧化应激和自噬调节之间的复杂相互作用，这些相互作用受到饮酒模式、营养状况以及遗传/环境因素等多种因素的影响，这凸显了进一步开展分子研究以揭示这些机制并制定针对性干预措施的必要性。
