Inhibition of vinyl carbamate-induced hepatotoxicity, mutagenicity, and tumorigenicity by isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2- yl)carbamoyl]acetate (YH439).
Inhibition of vinyl carbamate-induced hepatotoxicity, mutagenicity, and tumorigenicity by isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2- yl)carbamoyl]acetate (YH439).
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DOI：
10.1093/carcin/19.4.687
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发表时间：
1998-04
期刊：
影响因子：
4.7
通讯作者：
S. G. Kim;Y. Surh;Y. Sohn;J. Yoo;J. Lee;A. Liem;J. Miller
中科院分区：
文献类型：
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作者：
S. G. Kim;Y. Surh;Y. Sohn;J. Yoo;J. Lee;A. Liem;J. Miller
(Isopropyl-2-(1，3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2-基)氨基甲酰]乙酸酯(YH439)是一种用于治疗肝损伤的新型二硫代亚甲基丙二酸酯衍生物。该化合物已被发现在转录水平下调肝脏细胞色素P-450 2E1(CYP2E1)的表达(8)。大蒜中存在的某些有机硫化合物对化学诱导的致癌和诱变具有保护作用，其化学预防活性部分与抑制CYP2E1有关。作为确定YH439可能的化学预防潜力的计划的一部分，我们最初检查了它对氨基甲酸乙烯酯(VC)诱导的肝毒性的影响，VC是一种接近的致癌物质，优先被CYP2E1激活。一个单独的IP地址。雄性SD大鼠注射维生素C(125 mg/kg体重)后，血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶等酶的水平升高，导致严重的肝损伤。经VC处理的动物肝脏切片病理组织学评价显示，肝损伤主要表现为小叶中心坏死，并伴有肝窦充血。雄性SD大鼠Vc前2天、1天和4小时分别经口给予YH439(200 mg/kg体重)，可完全阻止该致癌物所致的肝损伤。在另一项实验中，YH439以剂量相关的方式抑制了Vc对大鼠肝微粒体介导的细菌致突变性。此外，用YH439经胃插管给CD-1雌性小鼠预处理，可减少VC诱发的皮肤癌变。
Isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol -2-yl)carbamoyl]acetate (YH439) is a novel dithioylidene malonate derivative developed for the treatment of hepatic injury. The compound has been found to down-regulate the expression of hepatic cytochrome P-450 2E1 (CYP2E1) at the transcriptional level (8). Certain organosulfur compounds present in garlic elicit protective effects on chemically induced carcinogenesis and mutagenesis and their chemopreventive activities are associated in part with inhibition of CYP2E1. As part of a program to determine the likely chemopreventive potential of YH439, we initially examined its effects on hepatotoxicity induced by vinyl carbamate (VC), a proximate carcinogen that is preferentially bioactivated by CYP2E1. A single i.p. injection of VC (125 mg/kg body wt) to male Sprague-Dawley rats resulted in severe hepatic lesions as demonstrated by elevated levels of serum enzymes such as alanine aminotransferase and aspartate aminotransferase. Histopathological evaluation of liver sections from VC-treated animals revealed that the hepatic damage mainly consisted of centrilobular necrosis with sinusoidal congestion. Oral administration of YH439 (200 mg/kg body wt) to male Sprague-Dawley rats 2 days, 1 day and 4 h prior to VC completely prevented the hepatic damage caused by this carcinogen. In another experiment, rat hepatic microsome-mediated bacterial mutagenicity of VC was suppressed by YH439 in a dose-related manner. Furthermore, pretreatment of female CD-1 mice with YH439 by gastric intubation resulted in diminution of VC-induced skin carcinogenesis.