Reply to Brewer: Liver-targeted ALDH2 inhibition may reduce alcohol-seeking behaviors with limited side effects.
Reply to Brewer: Liver-targeted ALDH2 inhibition may reduce alcohol-seeking behaviors with limited side effects.
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回复 Brewer：肝脏靶向 ALDH2 抑制可能会减少酗酒行为，且副作用有限。
DOI：
10.1073/pnas.2001049117
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发表时间：
2020
影响因子：
11.1
通讯作者：
Gao,Bin
中科院分区：
文献类型：
--
作者：
Guillot,Adrien;Koob,GeorgeF;Gao,Bin
我们很高兴读到布鲁尔博士的信（1）关于我们在PNAS上的论文（2）。由于篇幅所限，我们仅简要讨论了醛脱氢酶2（ALDH 2）抑制疗法治疗酒精使用者障碍（AUD）的现有知识。我们非常感谢Brewer博士详细阐述了在患者和动物模型中测试的ALDH 2抑制疗法领域的先前发现（1）。的确，ALDH 2基因型对酒精寻求行为的影响已经得到了很好的证明（3），并且已经开发了许多抑制ALDH 2活性的药物来治疗AUD（4）。例如，氰胺（以柠檬酸钙碳酰亚胺盐的形式）可以通过其活性代谢物抑制ALDH活性，并且在欧洲，加拿大和日本仍在治疗上用作酒精厌恶剂（Temposil）（4）。双硫仑和氰胺都是有效的ALDH抑制剂，因此通过治疗患者血液中乙醛蓄积产生的不愉快体验（例如恶心、心动过速、潮红），可作为饮酒的抑制剂（4）。与双硫仑相比，氰胺是二线药物，因为与双硫仑相比，它能产生更大的肝损伤（4）。正如Dr. Brewer所述，双硫仑治疗的调整显示出有希望的结果，监督双硫仑治疗目前仍然是该类药物中最有效的治疗（5，6）;然而，双硫仑治疗可能产生副作用，如肝毒性，神经病变和其他不良反应（7-9）。此外，尽管双硫仑已被重新用作抗癌剂（10），但长期双硫仑治疗可能导致酗酒者全身和局部乙醛水平升高，从而增加癌症发生的风险。通过使用肝脏特异性Aldh 2敲除小鼠和体内肝细胞Aldh 2表达敲除，我们证明了肝脏靶向方法可能足以减少酒精寻求行为，同时对其他代谢参数和整体身体功能的影响有限（2）。这种策略的主要好处包括限制对其他器官的副作用，以及由于毒性乙醛在全身血液循环和其他器官中积聚而导致的癌症。最后，这种方法可以通过限制循环乙醛水平增加的不良影响来有利于患者对治疗的依从性。由于许多方法可用于将治疗剂特异性递送至肝脏和肝细胞，例如修饰的脂质体、载脂蛋白、聚合物或病毒载体（11），因此特异性抑制肝脏中的ALDH 2是可行的，我们希望我们的研究可以作为开发肝脏靶向AUD治疗的基础。
We are pleased to read the Letter from Dr. Brewer (1) on our paper in PNAS (2). In our manuscript, we only briefly discuss our current knowledge about aldehyde dehydrogenase 2 (ALDH2) inhibition therapy for the treatment of alcohol user disorder (AUD) due to space limitation. We greatly appreciate Dr. Brewer for elaborating on previous findings in the area of ALDH2 inhibition therapies that were tested both in patients and in animal models (1). It is true that the effects of ALDH2 genotype on alcohol-seeking behavior have been well documented (3) and many drugs that inhibit ALDH2 activities have been developed to treat AUD (4). For example, cyanamide (in the form of calcium carbimide citrate salt) can inhibit ALDH activity via its active metabolite and is still used therapeutically as an alcohol-aversive agent (Temposil) in Europe, Canada, and Japan (4). Disulfiram and cyanamide both are potent ALDH inhibitors and thus act as alcohol-drinking deterrents, through unpleasant experiences (eg, nausea, tachycardia, flushing) produced by the accumulation of acetaldehyde in the blood of treated patients (4). Cyanamide is a second-line drug compared to disulfiram because of its capacity to produce greater liver damage compared with disulfiram (4). As described by Dr. Brewer, adjustments of the disulfiram therapy have shown promising results and supervised disulfiram treatment currently remains the most effective therapy in this drug class (5, 6); however, disulfiram therapy may generate side effects such as liver toxicity, neuropathies, and other adverse effects (7–9). In addition, although disulfiram has been repurposed as an anticancer agent (10), chronic disulfiram treatment may cause elevation of systemic and local acetaldehyde levels in alcoholics, thereby increasing the risk of cancer development. By using liver-specific Aldh2 knockout mice and in vivo hepatocyte-Aldh2 expression knockdown, we demonstrated that a liver-targeted approach might be sufficient to reduce alcohol-seeking behavior while having limited effects on other metabolic parameters and global body functions (2). Major benefits from such strategies include limiting side effects on other organs, and cancer due to toxic acetaldehyde buildup in the general blood circulation and in other organs. Finally, such an approach may favor patients’ compliance to treatment by limiting the unpleasant effects of increased circulating acetaldehyde levels. Because numerous approaches could be used to specifically deliver a therapeutic agent to the liver and to the hepatocytes, such as modified liposomes, apolipoproteins, polymers, or viral vectors (11), it is feasible to specifically inhibit ALDH2 in the liver, and we hope our study may serve as a basis for the development of liver-targeted AUD treatment.