研究找到预防药物伤肝新方法

tonychant

据美国物理学家组织网1月15日报道，最近，美国马萨诸塞州总医院（MGH）找到一种能保护肝脏免受扑热息痛等肝毒性药物伤害的新方法，提高相关药物的安全性。相关论文提前发表在《自然—生物技术》杂志网站上。

研究报告称，抑制一种细胞之间的通讯能保护肝脏，他们找到了一种能抑制肝细胞之间特殊间隙连接的小分子，能在服用肝毒性药物之时或之后，保护正常小鼠肝脏不受任何损伤并免于死亡。

肝毒性限制了许多药物开发，对临床医疗和制药工业都提出了很高的要求。在美国，药物性肝损伤是造成肝功能衰竭的最普遍原因，也使许多药物退出市场或在研发早期就被淘汰。目前，因无法预防，药物性肝损伤甚至限制了病人对治疗方案的选择。

新研究可能改变药物开发和制定的方向，带来肝毒性更小的药物，提高药物安全性。研究人员解释说，相邻两个细胞之间是通过间隙连接来进行交流的，间隙连接是相邻细胞之间的中空隧道。比如在心脏中，间隙连接能传播心肌收缩所需的电活动，但它们在肝脏中的功能还不明确。而研究小组最近发现，肝细胞间的某种间隙连接方式能把受损细胞发出的免疫信号传递给周边未受伤的细胞，使炎症和损伤扩大。他们根据实验找到了这些特殊的间隙连接目标，然后通过基因技术造出一些缺乏这种特殊间隙连接的小鼠，给它们和正常小鼠服用多种含有扑热息痛的肝毒性药物，如泰诺（Tylenol），相比之下，那些缺乏特殊肝细胞间隙连接的小鼠获得了一种保护，能免于肝损伤、发炎和死亡。

由此，研究小组找到了一种抑制干细胞间隙连接的小分子，能在服用肝毒性药物之时或服用之后，保护正常小鼠的肝脏不受任何损伤并免于死亡。此外，细胞培养实验还显示，封锁间隙连接能限制肝细胞损伤向外自由传播，缓解氧化压力，而这种机制可能提供显著的保护。

“这一发现为大量基础科研和临床应用提供了有利支持。”论文高级作者、MGH医疗工程中心主管马丁·雅玛什说，“但我们还在继续探索，在病人身上使用这种方法之前，还需要进一步研究这些间隙连接抑制剂的非目标效应，掌握更多暂时性封锁肝细胞特殊间隙连接隧道所产生的长期后果。”

马萨诸塞州总医院合作伙伴帕特尔还表示，这些发现有望带来一种全新的药物开发战略，跟选择间隙连接抑制剂结合起来，开发出高效无毒的药物。“我们希望这一新技术商业化，最终开发出对肝脏安全的医药用品，并更好地治疗药物性肝损伤。”（来源：科技日报）




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Mass. General researchers find novel way to prevent drug-induced liver injuryBlocking cell-to-cell communication may prevent liver damage and improve drug safety        Massachusetts General Hospital (MGH) investigators have developed a novel strategy to protect the liver from drug-induced injury and improve associated drug safety. In their report receiving advance online publication in the journal Nature Biotechnology, the team reports that inhibition of a type of cell-to-cell communication can protect against the damage caused by liver-toxic drugs such as acetaminophen.  
        "Our findings suggest that this therapy could be a clinically viable strategy for treating patients with drug-induced liver injury," says Suraj Patel, PhD, of the MGH Department of Surgery, the paper's lead author. "This work also has the potential to change the way drugs are developed and formulated, which could improve drug safety by providing medications with reduced risk of liver toxicity."
        Developing, approving and prescribing a drug requires that the therapeutic benefits be weighed against any potential toxicities. Liver toxicity limits the development of many therapeutic compounds and presents major challenges to both clinical medicine and to the pharmaceutical industry. Drug-induced liver injury is the most common cause of acute liver failure in the U.S. and is also the most frequent reason for abandoning drugs early in development or withdrawing them from the market. Since no pharmaceutical strategies currently exist for preventing drug-induced liver injury, treatment options are limited to discontinuing the offending drug, supportive care and transplantation for end-stage liver failure.
        Gap junctions are hollow channels that connect neighboring cells and allow direct intercellular communication between coupled cells. In the heart, gap junctions are known to propagate the electrical activity required for contraction, but their role in the liver is poorly defined. Recent work by the MGH team and others has shown that assemblies of intercellular gap junctions spread immune signals from injured liver cells to surrounding undamaged cells, amplifying overall inflammation and injury. The current study was designed to discover the potential of targeting liver-specific gap junctions to limit drug-induced liver injury.
        The researchers first used a strain of genetically mutated mice that lack a particular liver-specific gap junction. The mice were administered various liver-toxic drugs, such as the commonly used medicine acetaminophen. Overdoses of acetaminophen, which is best known under the brand name Tylenol, are the most frequent cause of drug-induced liver injury. Compared to normal mice, those lacking liver gap junctions were protected against liver damage, inflammation and death caused by administration of liver-toxic drugs.
        The team then identified a small-molecule inhibitor of liver gap junctions that, when given with or even after the toxic drugs, protected the livers of normal mice against any injury and prevented their death. Additionally, cell culture experiments indicated that blocking gap junctions limited the spread through liver cells of damaging free radicals and oxidative stress, suggesting a possible mechanism for the observed protection.     
         "This finding is very exciting and potentially very powerful from a number of basic science and clinical application standpoints, which we are continuing to explore," says Martin Yarmush, MD, PhD, director of the MGH Center for Engineering in Medicine and senior author of the study. "However, before we can think about applying this approach to patients, we need to know more about any off-target effects of these gap junction inhibitors and better understand the long-term ramifications of temporarily blocking liver-specific gap junction channels."
        A patent related to the work has been filed by Partners Healthcare, and an early stage biotechnology company, Heprotech Inc., was recently established to develop this new technology further. "The findings from this work suggest a novel drug development strategy in which therapeutically effective but potentially liver-toxic compounds could be co-formulated with selective gap junction inhibitors to improve their safety," explains Patel, a co-founder of Heprotech along with Yarmush. "We look forward to helping commercialize this new technology, with the ultimate goal of developing liver-safe pharmaceuticals and better treatments for drug-induced liver injury."
       

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Patel is a research fellow in the MGH Department of Surgery and Yarmush is a faculty member in the Harvard-MIT Division of Health Science. Additional co-authors of the study are Jack Milwid, PhD, Kevin King, MD, PhD, Stefan Bohr, MD, PhD, Arvin Iracheta-Vellve, Matthew Li, Antonia Vitalo, Biju Parekkadan, PhD, and Rohit Jindal, PhD, all with the MGH Center for Engineering in Medicine. The work was supported by grants from the National Institutes of Health and Shriners Hospitals for Children.
        Massachusetts General Hospital (www.massgeneral.org), founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $750 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.