6-(Methylsulfinyl)hexyl isothiocyanate protects acetaldehyde-caused cytotoxicity through the induction of aldehyde dehydrogenase in hepatocytes
6-(Methylsulfinyl)hexyl isothiocyanate protects acetaldehyde-caused cytotoxicity through the induction of aldehyde dehydrogenase in hepatocytes
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DOI：
10.1016/j.abb.2020.108329
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发表时间：
2020-06-15
影响因子：
3.9
通讯作者：
Ashida, Hitoshi
中科院分区：
文献类型：
--
作者：
Kitakaze, Tomoya;Yuan, Sihao;Ashida, Hitoshi
在体内，乙醇脱氢酶迅速将乙醇转化为其有毒的代谢物乙醛，乙醛再被醛脱氢酶（ALDH）代谢为无毒的乙酸。6-（甲基亚硫酰基）己基异硫氰酸酯（6- msitc）是山葵（Wasabia japonica）中的主要生物活性化合物，具有抗氧化、抗炎、抗癌等多种生理作用。然而，6-MSITC对酒精代谢的影响尚未得到研究。在本研究中，我们在体外和体内研究了6-MSITC对肝脏ALDH活性和蛋白表达的影响。6-MSITC抑制乙醇和乙醛诱导的细胞毒性。6-MSITC对HepG2细胞的处理通过诱导线粒体ALDH2表达而不是细胞质ALDH1A1表达增强了ALDH活性。敲低Nrf2可消除6- msitc诱导的ALDH2表达，表明Nrf2调节ALDH2的表达。此外，6-MSITC增加了Nrf2的核易位以及Nrf2调控的II期药物代谢酶HO-1和SOD2的表达水平。口服6-MSITC可提高C57BL/6J小鼠肝脏线粒体ALDH2活性及其表达。这些结果表明，6-MSITC可能通过Nrf2/ARE途径诱导线粒体ALDH2表达来保护肝细胞中的乙醛毒性。
In the body, alcohol dehydrogenase rapidly converts ethanol to its toxic metabolite, acetaldehyde, which is further metabolized to non-toxic acetic acid by aldehyde dehydrogenase (ALDH). 6-(methylsulfinyl)hexyl isothiocyanate (6-MSITC), a major bioactive compound in Wasabi (Wasabia japonica) has various physiological effects such as anti-oxidative, anti-inflammatory and anti-cancer effects. However, the effect of 6-MSITC on alcohol metabolism has not been studied. In this study, we investigated the effects of 6-MSITC on hepatic ALDH activity and protein expression both in vitro and in vivo. 6-MSITC inhibited ethanol- and acetaldehyde-induced cytotoxicity. Treatment with 6-MSITC to HepG2 cells enhanced ALDH activity through the induction of mitochondrial ALDH2 expression, but not cytosolic ALDH1A1. Knockdown of Nrf2 canceled the 6-MSITC-induced ALDH2 expression, indicating that Nrf2 regulated ALDH2 expression. Moreover, 6-MSITC increased the nuclear translocation of Nrf2 and the expression levels of HO-1 and SOD2, Nrf2-regulated phase II drug-metabolizing enzymes. Oral administration of 6-MSITC increased the mitochondrial ALDH2 activity and its expression in the liver of C57BL/6J mice. These results suggested that 6-MSITC is possible to protect acetaldehyde toxicity in hepatocytes by induction of mitochondrial ALDH2 expression through Nrf2/ARE pathway.