Shi Zhuangqi, Han Shuxin
Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, 830046, China.
Heliyon. 2025 Jan 2;11(1):e41629. doi: 10.1016/j.heliyon.2025.e41629. eCollection 2025 Jan 15.
Statins are widely used for treating lipid disorders and cardiovascular diseases. However, the therapeutic efficiency and adverse effects of statins vary among different patients, which numerous clinical and epidemiological studies have attributed to genetic polymorphisms in statin-metabolizing enzymes and transport proteins. The metabolic processes of statins are relatively complex, involving spontaneous or enzyme-catalyzed interconversion between more toxic lactone metabolites and active acid forms in the liver and bloodstream, influenced by multiple factors, including the expression levels of many metabolic enzymes and transporters. Addressing the variable statin therapeutic outcomes is a pressing clinical challenge. Transcription factors and epigenetic modifications regulate the metabolic enzymes and transporters involved in statin metabolism and disposition and, therefore, hold promise as 'personalized' targets for achieving optimized statin therapy. In this review, we explore the potential for customizing therapy by targeting the metabolism of statin medications. The biochemical bases of adverse reactions to statin drugs and their correlation with polymorphisms in metabolic enzymes and transporters are summarized. Next, we mainly focus on the regulatory roles of transcription factors and epigenetic modifications in regulating the gene expression of statin biochemical machinery. The recommendations for future therapies are finally proposed by targeting the central regulatory factors of statin metabolism.
他汀类药物被广泛用于治疗脂质紊乱和心血管疾病。然而，他汀类药物的治疗效果和不良反应在不同患者中存在差异，众多临床和流行病学研究将其归因于他汀类药物代谢酶和转运蛋白的基因多态性。他汀类药物的代谢过程相对复杂，涉及肝脏和血液中更具毒性的内酯代谢物与活性酸形式之间的自发或酶催化相互转化，受多种因素影响，包括许多代谢酶和转运蛋白的表达水平。应对他汀类药物治疗结果的变异性是一项紧迫的临床挑战。转录因子和表观遗传修饰调节参与他汀类药物代谢和处置的代谢酶和转运蛋白，因此有望成为实现优化他汀类药物治疗的“个性化”靶点。在本综述中，我们探讨了通过靶向他汀类药物代谢来定制治疗的潜力。总结了他汀类药物不良反应的生化基础及其与代谢酶和转运蛋白多态性的相关性。接下来，我们主要关注转录因子和表观遗传修饰在调节他汀类药物生化机制基因表达中的作用。最后，通过靶向他汀类药物代谢的核心调节因子，提出了未来治疗的建议。
