Off-target effects of statins: molecular mechanisms, side effects and the emerging role of kinases

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology Pub Date : 2024-08-24 DOI:10.1111/bph.17309

Francisco Alejandro Lagunas-Rangel, Edgars Liepinsh, Robert Fredriksson, Ahmed M. Alsehli, Michael J. Williams, Maija Dambrova, Jörgen Jönsson, Helgi B. Schiöth

{"title":"Off-target effects of statins: molecular mechanisms, side effects and the emerging role of kinases","authors":"Francisco Alejandro Lagunas-Rangel, Edgars Liepinsh, Robert Fredriksson, Ahmed M. Alsehli, Michael J. Williams, Maija Dambrova, Jörgen Jönsson, Helgi B. Schiöth","doi":"10.1111/bph.17309","DOIUrl":null,"url":null,"abstract":"<p>Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator-activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off-target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off-target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17309","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"British Journal of Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/bph.17309","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

Abstract

Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator-activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off-target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off-target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer.

Abstract Image

查看原文本刊更多论文

他汀类药物的脱靶效应：分子机制、副作用和激酶的新作用。

他汀类药物是最重要的药物类别之一。在这篇分析综述中，我们阐明了他汀类药物在靶向（针对 3-羟基-3-甲基戊二酰辅酶 A 还原酶 [HMGCR]）和非靶向效应方面错综复杂的分子机制和毒理学原理。他汀类药物与许多膜激酶（如表皮生长因子受体（EGFR）、erb-b2 受体酪氨酸激酶 2（HER2）和 MET 原癌基因、受体酪氨酸激酶（MET））以及细胞膜激酶（如 SRC 原癌基因、非受体酪氨酸激酶（Src））相互作用，并在纳摩尔浓度下显示出抑制活性。此外，在浓度较高时，它们还与钙 ATP 酶和过氧化物酶体增殖激活受体 α（PPARα/NR1C1）相互作用。他汀类药物与线粒体复合物 III 和 IV 相互作用，抑制辅酶 Q10 的合成也会损害复合物 I 和 II 的功能。他汀类药物是激酶、钙离子 ATP 酶和线粒体复合物的抑制剂，同时激活 PPARα。这些脱靶效应可能是他汀类药物治疗患者出现副作用的原因，包括肌肉骨骼症状和肝脏效应。有趣的是，他汀类药物的某些脱靶效应也可能是产生良好疗效的原因，这与他汀类药物在炎症性疾病和癌症等疾病中的再利用有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

British Journal of Pharmacology 医学-药学

CiteScore

15.40

自引率

12.30%

发文量

270

审稿时长

2.0 months

期刊介绍： The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.