Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
SITAC, Società Italiana per il Trattamento dell'Alcolismo e le sue Complicanze, Sapienza University of Rome, Rome, Italy.
Curr Med Chem. 2024;31(36):5837-5855. doi: 10.2174/0109298673256937231004093143.
Alcohol use disorders are responsible for 5.9% of all death annually and 5.1% of the global disease burden. It has been suggested that alcohol abuse can modify gene expression through epigenetic processes, namely DNA and histone methylation, histone acetylation, and microRNA expression. The alcohol influence on epigenetic mechanisms leads to molecular adaptation of a wide number of brain circuits, including the hypothalamus-hypophysis-adrenal axis, the prefrontal cortex, the mesolimbic-dopamine pathways and the endogenous opioid pathways. Epigenetic regulation represents an important level of alcohol-induced molecular adaptation in the brain. It has been demonstrated that acute and chronic alcohol exposure can induce opposite modifications in epigenetic mechanisms: acute alcohol exposure increases histone acetylation, decreases histone methylation and inhibits DNA methyltransferase activity, while chronic alcohol exposure induces hypermethylation of DNA. Some studies investigated the chromatin status during the withdrawal period and the craving period and showed that craving was associated with low methylation status, while the withdrawal period was associated with elevated activity of histone deacetylase and decreased histone acetylation. Given the effects exerted by ethanol consumption on epigenetic mechanisms, chromatin structure modifiers, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, might represent a new potential strategy to treat alcohol use disorder. Further investigations on molecular modifications induced by ethanol might be helpful to develop new therapies for alcoholism and drug addiction targeting epigenetic processes.
酒精使用障碍每年导致 5.9%的死亡和 5.1%的全球疾病负担。有人认为，酒精滥用可以通过表观遗传过程来改变基因表达，即 DNA 和组蛋白甲基化、组蛋白乙酰化和 microRNA 表达。酒精对表观遗传机制的影响导致了大量脑回路的分子适应，包括下丘脑-垂体-肾上腺轴、前额叶皮层、中脑边缘多巴胺途径和内源性阿片途径。表观遗传调控代表了酒精引起的大脑分子适应的一个重要水平。已经证明，急性和慢性酒精暴露可以在表观遗传机制中诱导相反的修饰：急性酒精暴露增加组蛋白乙酰化，减少组蛋白甲基化并抑制 DNA 甲基转移酶活性，而慢性酒精暴露诱导 DNA 超甲基化。一些研究调查了戒断期和渴求期的染色质状态，结果表明，渴求与低甲基化状态有关，而戒断期与组蛋白去乙酰化酶活性升高和组蛋白乙酰化减少有关。鉴于乙醇消耗对表观遗传机制的影响，染色质结构修饰剂，如组蛋白去乙酰化酶抑制剂和 DNA 甲基转移酶抑制剂，可能代表一种治疗酒精使用障碍的新潜在策略。进一步研究乙醇诱导的分子修饰可能有助于开发针对表观遗传过程的治疗酒精中毒和药物成瘾的新疗法。
