Determination of pharmacological inhibition of ALDH2 by ethanol clearance in mice.
Determination of pharmacological inhibition of ALDH2 by ethanol clearance in mice.
复制标题
测定小鼠体内乙醇清除对 ALDH2 的药理学抑制作用。
DOI：
10.1016/j.taap.2023.116801
复制
发表时间：
2024
影响因子：
3.8
通讯作者：
Amory,JohnK
中科院分区：
文献类型：
--
作者：
Haenisch,Michael;Paik,Jisun;Kim,Andy;Goldstein,Alex;Amory,JohnK
目的视黄酸在生殖、免疫、能量代谢和致癌等方面具有多种生理和病理生理作用。由于在某些疾病状态下抑制视黄酸生物合成的潜在益处，正在努力通过醛脱氢酶-1A（ALDH1A）家族的酶来开发视黄酸生物合成的抑制剂。然而，许多潜在的ALDH1A抑制剂也抑制在乙醇代谢中起作用的相关ALDH2酶。ALDH2抑制的准确的体外评估是有问题的，并且到目前为止，还没有确定候选ALDH1A inhibitors. Study designTo解决这个问题，我们开发了一种新的气相色谱-质谱乙醇清除试验，在小鼠中使用口服乙醇和乙醇随时间的连续测量。然后，我们用这种方法来确定候选ALDH1A inhibitors. ResultsEthanol清除在未经处理的雄性小鼠ALDH2的药理学抑制发生在60分钟内。与未处理的对照相比，用WIN 18，446（一种已知的ALDH 1A抑制剂，也抑制ALDH 2）处理的雄性小鼠表现出对乙醇清除的显著抑制。新的吡唑和哌嗪ALDH1A抑制剂，然后测试与哌嗪抑制剂证明ALDH2 inhibitionviaimpaired乙醇清除率，而吡唑抑制剂不干扰乙醇代谢，表明缺乏ALDH2 inhibition.ConclusionsInhibition乙醇清除率是一个usefulin vivomethod推断肝脏ALDH2的药理学抑制。该测定可用于开发用于多种治疗适应症的新型ALDH1A特异性抑制剂。
ObjectivesRetinoic acid plays diverse physiological and pathophysiological roles in reproduction, immune function, energy metabolism and carcinogenesis. Because of the potential benefits of inhibiting retinoic acid biosynthesis in certain disease states, efforts are underway to develop inhibitors of retinoic acid biosynthesisviainhibition of the aldehyde dehydrogenase-1 A (ALDH1A) family of enzymes. However, many potential ALDH1A inhibitors also inhibit the related ALDH2 enzyme that plays a role in the metabolism of ethanol. Accuratein vitroassessment of ALDH2 inhibition is problematic, and to date, there are no publishedin vivoassays to determine inhibition of ALDH2 by candidate ALDH1A inhibitors.Study designTo address this, we developed a novel gas-chromatography-mass-spectrometry ethanol clearance assay in mice using orally administered ethanol and serial measurement of ethanol over time. We then used this assay to determine pharmacological inhibition of ALDH2 by candidate ALDH1A inhibitors.ResultsEthanol clearance in untreated male mice occurs within sixty minutes. Male mice treated with WIN 18,446, a known ALDH1A inhibitor that also inhibits ALDH2, demonstrated significant inhibition of ethanol clearance compared to untreated controls. Novel pyrazole and piperazine ALDH1A inhibitors were then tested with the piperazine inhibitor demonstrating ALDH2 inhibitionviaimpaired ethanol clearance while the pyrazole inhibitor did not interfere with ethanol metabolism, suggesting a lack of ALDH2 inhibition.ConclusionsInhibition of ethanol clearance is a usefulin vivomethod of inferring pharmacologic inhibition of hepatic ALDH2. This assay may be useful in the development of novel ALDH1A specific inhibitors for a variety of therapeutic indications.
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